Pyrazole aminopyrimidine derivatives as lrrk2 modulators

ABSTRACT

Compounds of the formula I: 
     
       
         
         
             
             
         
       
         
         or pharmaceutically acceptable salts thereof, 
         wherein X, R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson&#39;s disease.

FIELD OF THE INVENTION

This invention pertains to compounds that modulate the function of LRRK2and are useful for treatment of LRRK2-mediated diseases and conditionssuch as Parkinson's disease.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases such as Parkinson's disease, Lewy bodydementia and Huntington's disease affect millions of individuals.Parkinson's disease is a chronic, progressive motor system disorder thatafflicts approximately one out of every 1000 people, with hereditaryParkinson's disease accounting for 5-10% of all of patients. Parkinson'sdisease is caused by progressive loss of mid-brain dopamine neurons,leaving patients with impaired ability to direct and control theirmovements. The primary Parkinson's disease symptoms are trembling,rigidity, slowness of movement, and impaired balance. Many Parkinson'sdisease patients also experience other symptoms such as emotionalchanges, memory loss, speech problems, and sleeping disorders.

The gene encoding the leucine-rich repeat kinase 2 protein (LRRK2) hasbeen identified in association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp 595-600; Zimprich etal., Neuron, Vol. 44(4), 2004, 601-607). In-vitro studies show thatParkinson's disease-associated mutation leads to increased LRRK2 kinaseactivity and decreased rate of GTP hydrolysis compared to wild-type (Guoet al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670.Anti-LRRK2 antibodies have been used to label brainstem Lewy bodiesassociated with Parkinson's disease and cortical antibodies associatedwith Lewis bodydementia suggesting that LRRK2 may play an important rolein Lewie body formation and pathogenesis associated with these diseases(Zhou et al., Molecular Degeneration, 2006, 1:17doi:10.1186/1750-1326-1-17). LRRK2 has also been identified as a genepotentially associated with increased susceptibility to Crohn's diseaseand susceptibility to leprosy (Zhang et al., New England J. Med. Vol.361 (2009) pp. 2609-2618.

LRRK2 has also been associated with the transition of mild cognitiveimpairment to Alzheimer's disease (WO2007/149789); L-Dopa induceddyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp.171-177; CNS disorders associated with neuronal progenitordifferentiation (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25);cancers such as kidney, breast, prostate, blood and lung cancers andacute myelogenous leukemia (WO2011/038572); papillary renal and thyroidcarcinomas (Looyenga et al.,www.pnas.org/cgi/doi/10.1073/pnas.1012500108); multiple myeloma (Chapmanet al., Nature Vol. 471, 2011, pp. 467-472); amyotrophic lateralsclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis “Early Online2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol.13(4), 2006, pp. 169-183); and ankylosing spondylytis (Danoy et al.,PLoS Genetics, Vol. 6(12), 2010, e1001195, pp. 1-5).

Accordingly, compounds and compositions effective at modulating LRRK2activity may provide a treatment for neurodegenerative diseases such asParkinson's disease and Lewie body dementia, for CNS disorders such asAlzheimer's disease and L-Dopa induced dyskinesia, for cancers such askidney, breast, prostate, blood, papillary and lung cancers, acutemyelogenous leukemia and multiple myeloma, and for inflammatory diseasessuch as leprosy, Crohn's disease, amyotrophic lateral sclerosis,rheumatoid arthritis, and ankylosing spondylytis. Particularly, there isa need for compounds with LRRK2 affinity that are selective for LRRK2over other kinases, such as JAK2, which can provide effective drugs fortreatment of neurodegenerative disorders such as PD.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

X is: —NR^(a)—; or —O— wherein R^(a) is hydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted oneor more times with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted one or more times withC₁₋₆alkyl; heterocyclyl optionally substituted one or more times withR⁷; or heterocyclyl-C₁₋₆alkyl optionally substituted one or more timeswith R⁷;

or X and R¹ together form C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three- to six-membered heterocyclic ring optionally substitutedone or more times with R⁷;

R² is: C₁₋₆alkyl; halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl optionally substitutedone or more times with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted one or more times withR⁶; —OR^(b) wherein R^(b) is C₁₋₆alkyl, C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶, or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted one or moretimes with R⁶; or —C(O)—R^(c) wherein R^(c) is C₁₋₆alkyl, C₁₋₆alkoxy,amino, or heterocyclyl optionally substituted one or more times with R⁷;

R³ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfonylC₁₋₆alkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶; heterocyclyl optionallysubstituted one or more times with R⁷; heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷; aryl optionally substituted one or more times with R⁸;aryl-C₁₋₆alkyl wherein the aryl portion is optionally substituted one ormore times with R⁸; heteroaryl optionally substituted one or more timeswith R⁸; heteroaryl-C₁₋₆alkyl wherein the heteroaryl portion isoptionally substituted one or more times with R⁸; or —Y—C(O)—R^(d);

Y is C₂₋₆alkylene or a bond;

R^(d) is C₁₋₆alkyl, C₁₋₆alkoxy, amino, C₁₋₆alkyl-amino,di-C₁₋₆alkyl-amino, halo-C₁₋₆alkyl-amino, di-halo-C₁₋₆alkyl-amino,halo-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy-C₁₋₆alkyl,cyano-C₁₋₆alkyl, C₁₋₆alkylsulfonylC₁₋₆alkyl, amino-C₁₋₆alkyl,C₃₋₆cycloalkyl optionally substituted one or more times with R⁶,C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶ heterocyclyl optionallysubstituted one or more times with R⁷, or heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷;

R⁴ is: hydrogen; C₁₋₆alkyl; halo; cyano; halo-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkynyl; C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶; or —Y—C(O)—R^(d);

R⁵ is: hydrogen; or C₁₋₆alkyl;

each R⁶ is independently: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; oxo;cyano; halo; or Y—C(O)—R^(d);

each R⁷ is independently: C₁₋₆alkyl; halo-C₁₋₆alkyl; halo; oxo;C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano;—Y—C(O)—R^(d); heterocyclyl; heterocyclyl-C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; or C₃₋₆cycloalkylsulfonyl; and

each R⁸ is independently: oxo; C₁₋₆alkyl; halo-C₁₋₆alkyl; halo;C₁₋₆alkyl-sulfonyl; C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl; cyano;hetoeryclyl; heterocyclyl-C₁₋₆alkyl; —Y—C(O)—R^(d); C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, or C₃₋₆cycloalkyl-sulfonyl.

The invention also provides pharmaceutical compositions comprising thecompounds, methods of using the compounds, and methods of preparing thecompounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R isalkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R isalkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein Ris alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ whereinR is alkylene and R′ is alkoxy as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula—O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as definedherein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R isalkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein Ris alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂—R, wherein R is alkylas defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—SO₂—R″ where R′ isalkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein Ris alkylene and R′ is alkyl as defined herein.

“Amino means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen or alkyl as defined herein. “Amino thusincludes “alkylamino (where one of R and R′ is alkyl and the other ishydrogen) and “dialkylamino (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof, each being optionallysubstituted.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, meansa group of the formula —C(O)—OH.

“Cyanoalkyl” “means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Particular cycloalkyl are unsubstituted orsubstituted with alkyl. Cycloalkyl can optionally be substituted withone or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated (cycloalkenyl) derivatives thereof

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof, eachoptionally substituted.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, for example, one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be usedinterchangeably, means an alkyl as defined herein that is substituted atleast once with hydroxy and at least once with alkoxy. “Alkoxyhydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example,2-hydroxy-3-methoxy-propan-1-yl and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl,heteroaryl, cycloalkyl or heterocyclyl which is optionally substitutedindependently with one to four substituents, for example one or twosubstituents selected from alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,heteroalkyl, —COR, —SO₂R (where R is hydrogen, alkyl, phenyl orphenylalkyl), —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or—(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R^(a) and R^(b) are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl). Certain particular optionalsubstituents for “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or“heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino andalkylsulfonyl. In one embodiment substituents are methyl, fluoro,chloro, trifluoromethyl, methoxy, amino and methanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Parkinson's disease” means a degenerative disorder of the centralnervous system that impairs motor skills, speech, and/or cognitivefunction. Symptoms of Parkinson's disease may include, for example,muscle rigidity, tremor, slowing of physical movement (bradykinesia) andloss of physical movement (akinesia).

“Lewie (Lewy) body disease” also called “Lewie body dementia”, diffuseLewie body disease”, cortical Lewie body disease”, means aneurogenerative disorder characterized anatomically by the presence ofLewie bodies in the brain.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as particular definitions, if any.

“Treating” or “treatment” of a disease state includes, inter alia,inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms, and/or relieving the diseasestate, i.e., causing temporary or permanent regression of the diseasestate or its clinical symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen sulfur or nitrogen atom in the structures hereinindicates the presence of a hydrogen atom unless indicated otherwise.Where a nitrogen-containing heteroaryl ring is shown with an openvalency on a nitrogen atom, and variables such as R^(a), R^(b) or R^(c)are shown on the heteroaryl ring, such variables may be bound or joinedto the open valency nitrogen. Where one or more chiral centers exists ina structure but no specific stereochemistry is shown for the chiralcenters, both enantiomers associated with each such chiral center areencompassed by the structure. Where a structure shown herein may existin multiple tautomeric forms, all such tautomers are encompassed by thestructure. The atoms represented in the structures herein are intendedto encompass all naturally occurring isotopes of such atoms. Thus, forexample, the hydrogen atoms represented herein are meant to includedeuterium and tritium, and the carbon atoms are meant to include C¹³ andC¹⁴ isotopes.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

X is: —NR^(a)—; or —O— wherein R^(a) is hydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted oneor more times with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted one or more times withC₁₋₆alkyl; heterocyclyl optionally substituted one or more times withR⁷; or heterocyclyl-C₁₋₆alkyl optionally substituted one or more timeswith R⁷;

or X and R¹ together form C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three- to six-membered heterocyclic ring optionally substitutedone or more times with R⁷;

R² is: C₁₋₆alkyl; halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl optionally substitutedone or more times with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted one or more times withR⁶; —OR^(b) wherein R^(b) is C₁₋₆alkyl, C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶, or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted one or moretimes with R⁶; or —C(O)—R^(c) wherein R^(c) is C₁₋₆alkyl, C₁₋₆alkoxy,amino, or heterocyclyl optionally substituted one or more times with R⁷;

R³ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfonylC₁₋₆alkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶; heterocyclyl optionallysubstituted one or more times with R⁷; heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷; aryl optionally substituted one or more times with R⁸;aryl-C₁₋₆alkyl wherein the aryl portion is optionally substituted one ormore times with R⁸; heteroaryl optionally substituted one or more timeswith R⁸; heteroaryl-C₁₋₆alkyl wherein the heteroaryl portion isoptionally substituted one or more times with R⁸; or —Y—C(O)—R^(d);

Y is C₂₋₆alkylene or a bond;

R^(d) is C₁₋₆alkyl, C₁₋₆alkoxy, amino, C₁₋₆alkyl-amino,di-C₁₋₆alkyl-amino, halo-C₁₋₆alkyl-amino, di-halo-C₁₋₆alkyl-amino,halo-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy-C₁₋₆alkyl,cyano-C₁₋₆alkyl, C₁₋₆alkylsulfonylC₁₋₆alkyl, amino-C₁₋₆alkyl,C₃₋₆cycloalkyl optionally substituted one or more times with R⁶,C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶ heterocyclyl optionallysubstituted one or more times with R⁷, or heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷;

R⁴ is: hydrogen; C₁₋₆alkyl; halo; cyano; halo-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkynyl; C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶; or —Y—C(O)—R^(d);

R⁵ is: hydrogen; or C₁₋₆alkyl;

each R⁶ is independently: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; oxo;cyano; halo; or Y—C(O)—R^(d);

each R⁷ is independently: C₁₋₆alkyl; halo-C₁₋₆alkyl; halo; oxo;C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano;—Y—C(O)—R^(d); heterocyclyl; heterocyclyl-C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; or C₃₋₆cycloalkylsulfonyl; and

each R⁸ is independently: oxo; C₁₋₆alkyl; halo-C₁₋₆alkyl; halo;C₁₋₆alkyl-sulfonyl; C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl; cyano;hetoeryclyl; heterocyclyl-C₁₋₆alkyl; —Y—C(O)—R^(d); C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, or C₃₋₆cycloalkyl-sulfonyl.

In certain embodiments the invention provides compounds of the formulaII:

or pharmaceutically acceptable salts thereof,wherein:

X is: —NR^(a)—; or —O— wherein R^(a) is hydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; heterocyclyl; orheterocyclyl-C₁₋₆alkyl;

or X and R¹ together form C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three- to six-membered heterocyclic ring.

R² is: C₁₋₆alkyl; halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl optionally substitutedwith C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkylportion is optionally substituted with C₁₋₆alkyl; —OR^(b) wherein R^(b)is C₁₋₆alkyl, C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl, orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl;

R³ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfonylalkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; heterocyclyl;heterocyclyl-C₁₋₆alkyl; aryl; heteroaryl; or —C(O)—R^(c) wherein R^(c)is C₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl;

R⁴ is: hydrogen; C₁₋₆alkyl; halo; cyano; halo-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkynyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl; or—C(O)—R^(c) wherein R^(c) is C₁₋₆alkyl, C₁₋₆alkoxy, amino, orheterocyclyl; and

R⁵ is: hydrogen; or C₁₋₆alkyl.

In certain embodiments of formula I or formula II, X is —NR^(a)— or —O—.

In certain embodiments of formula I or formula II, X is —NR^(a).

In certain embodiments of formula I or formula II, X is —O—.

In certain embodiments of formula I or formula II, X is —NH— or —O—.

In certain embodiments of formula I or formula II, X is —NH—.

In certain embodiments of formula I or formula II, X is —O—.

In certain embodiments of formula I or formula II, R^(a) is hydrogen.

In certain embodiments of formula I or formula II, R^(a) is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; heterocyclyl; orheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; orC₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is C₁₋₆alkyl orhalo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ isamino-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ isC₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is heterocyclyl orheterocyclyl-C₁₋₆alkyl.

In embodiments of formula I or formula II wherein R¹ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl or oxetanyl, each optionally substituted as definedherein.

In embodiments of formula I or formula II wherein R¹ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be tetrahydropyranyl,piperidinyl, tetrahydrofuranyl or oxetanyl, each optionally substitutedas defined herein.

In certain embodiments of formula I or formula II, R¹ istetrahydrofuranyl.

In certain embodiments of formula I or formula II, R¹ istetrahydropyranyl.

In certain embodiments of formula I or formula II, R¹ istetrahydrofuranyl-C₁₋₆alkyl or oxetanyl.

In certain embodiments of formula I or formula II, R¹ istetrahydrofuranyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is oxetanyl.

In certain embodiments of formula I or formula II, R¹ is oroxetan-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R¹ is: methyl; ethyl;n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl;cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl;cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl;oxetanyl; tetrahydropyranyl; 2,2-difluoroethyl; ortetrahydrofuranylmethyl.

In certain embodiments of formula I or formula II, R¹ is: methyl; ethyl;n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl;cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl;cyclopropylethyl; methoxyethyl; oxetanyl; tetrahydropyranyl;2,2-difluoroethyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I or formula II, R¹ is: methyl; ethyl;n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl;cyclohexyl; cyclopentylmethyl; methoxyethyl; oxetanyl;tetrahydropyranyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I or formula II, R¹ is2,2-difluoroethyl.

In certain embodiments of formula I or formula II, R¹ is: methyl; ethyl;n-propyl; isopropyl; or isobutyl.

In certain embodiments of formula I or formula II, R¹ is methyl orethyl.

In certain embodiments of formula I or formula II, R¹ is methyl.

In certain embodiments of formula I or formula II, R¹ is ethyl.

In certain embodiments of formula I or formula II, R¹ is: cyclopropyl;cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl;cyclobutylmethyl; cyclopentylmethyl; or cyclopropylethyl.

In certain embodiments of formula I or formula II, R¹ is: cyclopentyl;cyclohexyl; or cyclopentylmethyl.

In certain embodiments of formula I or formula II, R¹ is: cyclopropyl.

In certain embodiments of formula I or formula II, R¹ and R^(a) togetherwith the atoms to which they are attached may form a three- tosix-membered heterocyclic ring.

In certain embodiments of formula I or formula II, R¹ and R^(a) togetherwith the atoms to which they are attached may form a three-memberedheterocyclic ring.

In certain embodiments of formula I or formula II, R¹ and R^(a) togetherwith the atoms to which they are attached may form a four-memberedheterocyclic ring.

In certain embodiments of formula I or formula II, R¹ and R^(a) togetherwith the atoms to which they are attached may form a five-memberedheterocyclic ring.

In certain embodiments of formula I or formula II, R¹ and R^(a) togetherwith the atoms to which they are attached may form a six-memberedheterocyclic ring.

In certain embodiments of formula I or formula II, X and R¹ togetherform C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, X and R¹ togetherform C₁₋₆alkyl.

In certain embodiments of formula I or formula II, X and R¹ togetherform C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, X and R¹ togetherform C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is: C₁₋₆alkyl;halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; —OR^(b) wherein R^(b) isC₁₋₆alkyl, C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl, orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; or —C(O)—R^(c).

In certain embodiments of formula I or formula II, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; cyano; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is: halo;halo-C₁₋₆alkyl or cyano.

In certain embodiments of formula I or formula II, R² is: fluoro; bromo;chloro; iodo; trifluoromethyl; or cyano.

In certain embodiments of formula I or formula II, R² is: chloro;trifluoromethyl; or cyano.

In certain embodiments of formula I or formula II, R² is: halo; orhalo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is halo.

In certain embodiments of formula I or formula II, R² is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R² ishalo-C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R² is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is C₃₋₆cycloalkyl.

In certain embodiments of formula I or formula II, R² isC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² istetrahydrofuranyl.

In certain embodiments of formula I or formula II, R² istetrahydrofuranyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is oxetanyl.

In certain embodiments of formula I or formula II, R² isoxetan-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R² is fluoro, chloroor bromo.

In certain embodiments of formula I or formula II, R² is chloro.

In certain embodiments of formula I or formula II, R² is fluoro.

In certain embodiments of formula I or formula II, R² is bromo.

In certain embodiments of formula I or formula II, R² is bromo.

In certain embodiments of formula I or formula II, R² is iodo.

In certain embodiments of formula I or formula II, R² istrifluoromethyl.

In certain embodiments of formula I or formula II, R² is methoxy.

In certain embodiments of formula I or formula II, R² is cyano.

In certain embodiments of formula I or formula II, R² is C₂₋₆alkynyl.

In certain embodiments of formula I or formula II, R² is C₂₋₆alkenyl.

In certain embodiments of formula I or formula II, R² is —OR^(b) whereinR^(b) is C₁₋₆alkyl, C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkylportion is optionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I, R² is —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl; C₁₋₆alkylsulfonyl;C₁₋₆alkylsulfonylC₁₋₆alkyl; amino-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted one or more timeswith R⁶; heterocyclyl optionally substituted one or more times with R⁷;heterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion is optionallysubstituted one or more times with R⁷; aryl optionally substituted oneor more times with R⁸; heteroaryl optionally substituted one or moretimes with R⁸; or —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, R³ is: hydrogen;C₁₋₆alkyl; halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl; C₁₋₆alkylsulfonyl;C₁₋₆alkylsulfonylalkyl; amino-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;heterocyclyl; heterocyclyl-C₁₋₆alkyl; aryl; heteroaryl; or —C(O)—R^(c).

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;heterocyclyl; heterocyclyl-C₁₋₆alkyl; or —C(O)—R^(b) wherein R^(b) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;heterocyclyl; heterocyclyl-C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted one or more timeswith R⁶; heterocyclyl optionally substituted one or more times with R⁷;heterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion is optionallysubstituted one or more times with R⁷; or —C(O)—R^(d).

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl;heterocyclyl-C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) is C₁₋₆alkyl,C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;hydroxy-C₁₋₆alkyl;

C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is: C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; or C₁₋₆alkoxy-C₁₋₆alkyl.

In embodiments of formula I or formula II wherein R³ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl or oxetanyl.

In embodiments of formula I or formula II wherein R³ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl,tetrahydrofuranyl or oxetanyl, each optionally substituted one or moretimes, or one or two times, with R⁷ as defined herein.

In embodiments of formula I or formula II wherein R³ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or oxetanyl.

In embodiments of formula I or formula II wherein R³ is heterocyclyl orheterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,pyrrolidinyl, azetidinyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl or oxetanyl, each optionally substituted one or moretimes, or one or two times, with R⁷ as defined herein.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl;2-(morpholin-4-yl)-ethyl; 2-hydroxy-2-methyl-propan-1-yl;tetrahydropyran-4-yl; or morpholin-4-yl-carbonyl.

In certain embodiments of formula I, R³ is: methyl; ethyl; n-propyl;isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2-(morpholin-4-yl)-ethyl;2-hydroxy-2-methyl-propan-1-yl; or tetrahydropyran-4-yl.

In certain embodiments of formula I or formula II, R³ is hydrogen.

In certain embodiments of formula I or formula II, R³ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is C₂₋₆alkenyl.

In certain embodiments of formula I or formula II, R³ is C₂₋₆alkynyl.

In certain embodiments of formula I or formula II, R³ ishydroxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is C₃₋₆cycloalkyloptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R³ is C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R³ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is heterocyclyloptionally substituted one or more times with R⁷.

In certain embodiments of formula I or formula II, R³ is heterocyclyl.

In certain embodiments of formula I or formula II, R³ isheterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion is optionallysubstituted one or more times with R⁷.

In certain embodiments of formula I or formula II, R³ isheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is —C(O)—R^(c).

In certain embodiments of formula I or formula II, R³ iscyano-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ isC₁₋₆alkylsulfonyl.

In certain embodiments of formula I or formula II, R³ isC₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ isamino-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R³ is aryl optionallysubstituted one or more times with R⁸.

In certain embodiments of formula I or formula II, R³ is aryl.

In certain embodiments of formula I or formula II, R³ is phenyloptionally substituted one or more times, or one or two times, with R⁸.

In certain embodiments of formula I or formula II, R³ is heteroaryloptionally substituted one or more times, or one or two times, with R⁸.

In certain embodiments of formula I or formula II, R³ is heteroaryl.

In certain embodiments of formula I or formula II, R³ isC₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶

In certain embodiments of formula I or formula II, R³ is: hydrogen;methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl;cyclobutyl; methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl;sec-butylsulfonyl; morpholin-4-yl-ethyl; oxetan-3-yl; 2-methoxyethyl;2-hydroxy-2-methyl-propyl; 3-hydroxy-2-methyl-propan-2-yl;2-methoxy-propyl; tetrahydro-2H-pyran-4-yl; tetrahydrofuran-3-yl;2,6-dimethyltetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-3-yl); phenyl;4-(methylsulfonyl)phenyl); 4-cyano-phenyl; 4-fluoro-phenyl;4-chloro-phenyl; 3,5-difluorophenyl; 4-(dimethylamino-carbonyl)-phenyl);4-(cyclopropylsulfonyl)phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl;difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl;1-methyl-cyclopropyl-carbonyl; 3-methylpyridin-4-yl;2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl;pyridin-2-ylmethyl; 1-(pyridin-2-yl)ethyl; cyclopropylsulfonyl;1-cyano-1-methyl-ethyl (also called 2-cyano-propan-2-yl); 2-cyano-ethyl;1-cyano-ethyl; 2-cyano-2-methyl-propyl;1-(2,2,2-trifluoroethyl)piperidin-4-yl; 1-(methylsulfonyl)azetidin-3-yl;(3-methyloxetan-3-yl)methyl; (1 S,5S)-8-oxabicyclo[3.2.1]octan-3-yl;1-(oxetan-3-yl)piperidin-4-yl; 1-acetyl-piperidin-4-yl;1-(cyclopropyl-carbonyl)-piperidin-4-yl; 1-methyl-piperidin-4-yl;1-methyl-2-oxo-piperidin-5-yl; 2-oxo-piperidin-5-yl;1-(isopropyl-carbonyl)-piperidin-4-yl; 1-(oxetan-3-yl)azetidin-3-yl;1-(cyclopropyl-carbonyl)-piperidin-4-yl; 2-methoxycyclopentyl;3-methoxycyclopentyl; 1-methoxy-2-methylpropan-2-yl;tetrahydro-2H-1,1-dioxo-thiopyran-4-yl;3-fluoro-1-(oxetan-3-yl)piperidin-4-yl; 1-methoxypropan-2-yl;1-(2,2,2-trifluoroethyl)azetidin-3-yl); 1-(oxetan-3-yl)pyrrolidin-3-yl;1-isopropylazetidin-3-yl; 3-fluoro-1-methylpiperidin-4-yl;1-ethyl-3-fluoropiperidin-4-yl; 1-methylpyrrolidin-3-yl;2-methoxyethyl)piperidin-4-yl); 1-methyl-1-(methylamino-carbonyl)-ethyl;2-methyl-2-morpholino-propyl; 4,4-difluorocyclohexyl;morpholin-4-yl-carbonyl; dimethylamino-carbonyl-methyl;methylamino-carbonyl-methyl; 1-methyl-1-(dimethylamino-carbonyl)-ethyl;pyrrolidin-′-yl-carbonyl; 1-cyamo-cyclopropyl;1-(pyrrolidin-′-yl-carbonyl)-ethyl; 1-(dimethylamino-carbonyl)-ethyl;1-(methoxy-carbonyl)-ethyl; 1-(tert-butylamino-carbonyl)-1-methyl-ethyl;1-(2,2,2-trifluoroethyllamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-1-methyl-ethyl;1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-cyclobutyl;1-(isopropylamino-carbonyl)-1-methyl-ethyl; 1-cyano-cyclobutyl;2-methoxy-1-methyl-ethyl; 1-methyl-1-(methoxy-carbonyl)-ethyl;2-methoxy-2-methyl-propan-1-yl; 1-(oxetan-3-yl)-pyrrolidin-3-yl;isopropylsulfonyl; butane-2-sulfonyl; 1-(2-fluoroethyl)-piperidin-4-yl;3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl;pyridin-3-ylmethyl; 6-methyl-pyridin-2-ylmethyl;2-(morpholin-1-yl)-1,1,dimethyl-ethyl; pyrimdin-2-yl-methyl;3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl; 1-(oxetan-3-yl)-piperidin-3-yl;1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl; pyridazin-3-ylmethyl;piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl-butan-1-yl;1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl; pyrimidin-4-ylmethyl;1-methyl-1H-pyrazol-3-ylmethyl;1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl;1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl;3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl;dimethyl-[1,3]dioxan-5-yl, 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl;2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-5-yl;2-(4H-1,2,4-triazol-3-yl)propan-2-yl; or 1-methyl-1H-pyrazole-4-yl.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl; cyclobutyl;methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl; sec-butylsulfonyl;morpholin-4-yl-ethyl; oxetan-3-yl; 2-methoxyethyl;2-hydroxy-2-methyl-propyl; 3-hydroxy-2-methyl-propan-2-yl;2-methoxy-propyl; tetrahydro-2H-pyran-4-yl; tetrahydrofuran-3-yl;2,6-dimethyltetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-3-yl); phenyl;4-(methylsulfonyl)phenyl); 4-cyano-phenyl; 4-fluoro-phenyl;4-chloro-phenyl; 3,5-difluorophenyl; 4-(dimethylamino-carbonyl)-phenyl);4-(cyclopropylsulfonyl)phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl;difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl;1-methyl-cyclopropyl-carbonyl; 3-methylpyridin-4-yl;2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl;pyridin-2-ylmethyl; 1-(pyridin-2-yl)ethyl; cyclopropylsulfonyl;1-cyano-1-methyl-ethyl (also called 2-cyano-propan-2-yl); 2-cyano-ethyl;1-cyano-ethyl; 2-cyano-2-methyl-propyl;1-(2,2,2-trifluoroethyl)piperidin-4-yl; 1-(methylsulfonyl)azetidin-3-yl;(3-methyloxetan-3-yl)methyl; (1S,5S)-8-oxabicyclo[3.2.1]octan-3-yl;1-(oxetan-3-yl)piperidin-4-yl; 1-acetyl-piperidin-4-yl;1-(cyclopropyl-carbonyl)-piperidin-4-yl; 1-methyl-piperidin-4-yl;1-methyl-2-oxo-piperidin-5-yl; 2-oxo-piperidin-5-yl;1-(isopropyl-carbonyl)-piperidin-4-yl; 1-(oxetan-3-yl)azetidin-3-yl;1-(cyclopropyl-carbonyl)-piperidin-4-yl; 2-methoxycyclopentyl;3-methoxycyclopentyl; 1-methoxy-2-methylpropan-2-yl;tetrahydro-2H-1,1-dioxo-thiopyran-4-yl;3-fluoro-1-(oxetan-3-yl)piperidin-4-yl; 1-methoxypropan-2-yl;1-(2,2,2-trifluoroethyl)azetidin-3-yl); 1-(oxetan-3-yl)pyrrolidin-3-yl;1-isopropylazetidin-3-yl; 3-fluoro-1-methylpiperidin-4-yl;1-ethyl-3-fluoropiperidin-4-yl; 1-methylpyrrolidin-3-yl;2-methoxyethyl)piperidin-4-yl); 1-methyl-1-(methylamino-carbonyl)-ethyl;2-methyl-2-morpholino-propyl; 4,4-difluorocyclohexyl;morpholin-4-yl-carbonyl; dimethylamino-carbonyl-methyl;methylamino-carbonyl-methyl; 1-methyl-1-(dimethylamino-carbonyl)-ethyl;pyrrolidin-′-yl-carbonyl; 1-cyamo-cyclopropyl;1-(pyrrolidin-′-yl-carbonyl)-ethyl; 1-(dimethylamino-carbonyl)-ethyl;1-(methoxy-carbonyl)-ethyl; 1-(tert-butylamino-carbonyl)-1-methyl-ethyl;1-(2,2,2-trifluoroethyllamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-1-methyl-ethyl;1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-cyclobutyl;1-(isopropylamino-carbonyl)-1-methyl-ethyl; 1-cyano-cyclobutyl;2-methoxy-1-methyl-ethyl; 1-methyl-1-(methoxy-carbonyl)-ethyl;2-methoxy-2-methyl-propan-1-yl; 1-(oxetan-3-yl)-pyrrolidin-3-yl;isopropylsulfonyl; butane-2-sulfonyl; 1-(2-fluoroethyl)-piperidin-4-yl;3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl;pyridin-3-ylmethyl; 6-methyl-pyridin-2-ylmethyl;2-(morpholin-1-yl)-1,1,dimethyl-ethyl; pyrimdin-2-yl-methyl;3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl; 1-(oxetan-3-yl)-piperidin-3-yl;1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl; pyridazin-3-ylmethyl;piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl-butan-1-yl;1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl; pyrimidin-4-ylmethyl;1-methyl-1H-pyrazol-3-ylmethyl;1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl;1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl;3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl;dimethyl-[1,3]dioxan-5-yl; 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl;2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-5-yl;2-(4H-1,2,4-triazol-3-yl)propan-2-yl; or 1-methyl-1H-pyrazole-4-yl.

In certain embodiments of formula I or formula II, R³ is: hydrogen;methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl;2-hydroxy-2-methyl-propan-1-yl; tetrahydropyran-4-yl; ormorpholin-4-yl-carbonyl.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl;2-hydroxy-2-methyl-propan-1-yl; or tetrahydropyran-4-yl.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula I or formula II, R³ is: methyl; ethyl;or isopropyl.

In certain embodiments of formula I or formula II, R³ is hydrogen.

In certain embodiments of formula I or formula II, R³ is methyl.

In certain embodiments of formula I or formula II, R³ is ethyl.

In certain embodiments of formula I or formula II, R³ is n-propyl.

In certain embodiments of formula I or formula II, R³ is isopropyl.

In certain embodiments of formula I or formula II, R³ is2-methoxy-ethyl.

In certain embodiments of formula I or formula II, R³ is oxetan-3-yl.

In certain embodiments of formula I or formula II, R³ is2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula I or formula II, R³ istetrahydropyran-4-yl.

In certain embodiments of formula I or formula II, R³ ismorpholin-4-yl-carbonyl.

In certain embodiments of formula I or formula II, R³ is butyl.

In certain embodiments of formula I or formula II, R³ is cyclopropyl.

In certain embodiments of formula I or formula II, R³ iscyclopropylmethyl.

In certain embodiments of formula I or formula II, R³ is cyclobutyl.

In certain embodiments of formula I or formula II, R³ ismethanesulfonyl.

In certain embodiments of formula I or formula II, R³ is ethylsulfonyl.

In certain embodiments of formula I or formula II, R³ iscyclopropylsulfonyl.

In certain embodiments of formula I or formula II, R³ issec-butylsulfonyl.

In certain embodiments of formula I or formula II, R³ ismorpholin-4-yl-ethyl.

In certain embodiments of formula I or formula II, R³ is2-hydroxy-2-methyl-propyl.

In certain embodiments of formula I or formula II, R³ is3-hydroxy-2-methyl-propan-2-yl.

In certain embodiments of formula I or formula II, R³ is2-methoxy-propyl.

In certain embodiments of formula I or formula II, R³ istetrahydro-2H-pyran-4-yl.

In certain embodiments of formula I or formula II, R³ istetrahydrofuran-3-yl.

In certain embodiments of formula I or formula II, R³ is2,6-dimethyltetrahydro-2H-pyran-4-yl.

In certain embodiments of formula I or formula II, R³ istetrahydro-2H-pyran-3-yl).

In certain embodiments of formula I or formula II, R³ is phenyl.

In certain embodiments of formula I or formula II, R³ is4-(methylsulfonyl)phenyl).

In certain embodiments of formula I or formula II, R³ is 4-cyano-phenyl.

In certain embodiments of formula I or formula II, R³ is4-fluoro-phenyl.

In certain embodiments of formula Iv, R³ is 4-chloro-phenyl.

In certain embodiments of formula I or formula II, R³ is3,5-difluorophenyl.

In certain embodiments of formula I or formula II, R³ is4-(dimethylamino-carbonyl)-phenyl).

In certain embodiments of formula I or formula II, R³ is4-(cyclopropylsulfonyl)phenyl.

In certain embodiments of formula I or formula II, R³ is2,2,2-trifluoroethyl.

In certain embodiments of formula I or formula II, R³ is 2-fluoroethyl.

In certain embodiments of formula I or formula II, R³ is difluoromethyl.

In certain embodiments of formula I or formula II, R³ is2-dimethyl-1,3-dioxan-5-yl.

In certain embodiments of formula I or formula II, R³ is1-methyl-cyclopropyl-carbonyl.

In certain embodiments of formula I or formula II, R³ is3-methylpyridin-4-yl.

In certain embodiments of formula I or formula II, R³ is2-methylpyridin-4-yl.

In certain embodiments of formula I or formula II, R³ is pyridin-2-yl.

In certain embodiments of formula I or formula II, R³ is pyrimidin-2-yl.

In certain embodiments of formula I or formula II, R³ is pyrimidin-5-yl.

In certain embodiments of formula I or formula II, R³ ispyridin-2-ylmethyl.

In certain embodiments of formula I or formula II, R³ is1-(pyridin-2-yl)ethyl.

In certain embodiments of formula I or formula II, R³ iscyclopropylsulfonyl.

In certain embodiments of formula I or formula II, R³ is1-cyano-1-methyl-ethyl (also called 2-cyano-propan-2-yl).

In certain embodiments of formula I or formula II, R³ is 2-cyano-ethyl.

In certain embodiments of formula I or formula II, R³ is 1-cyano-ethyl.

In certain embodiments of formula I or formula II, R³ is2-cyano-2-methyl-propyl.

In certain embodiments of formula I or formula II, R³ is1-(2,2,2-trifluoroethyl)piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-(methylsulfonyl)azetidin-3-yl.

In certain embodiments of formula I or formula II, R³ is(3-methyloxetan-3-yl)methyl.

In certain embodiments of formula I or formula II, R³ is(1S,5S)-8-oxabicyclo[3.2.1]octan-3-yl.

In certain embodiments of formula I or formula II, R³ is1-(oxetan-3-yl)piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-acetyl-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-(cyclopropyl-carbonyl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-methyl-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-methyl-2-oxo-piperidin-5-yl.

In certain embodiments of formula I or formula II, R³ is2-oxo-piperidin-5-yl.

In certain embodiments of formula I or formula II, R³ is1-(isopropyl-carbonyl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-(oxetan-3-yl)azetidin-3-yl.

In certain embodiments of formula I or formula II, R³ is1-(cyclopropyl-carbonyl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is2-methoxycyclopentyl.

In certain embodiments of formula I or formula II, R³ is3-methoxycyclopentyl.

In certain embodiments of formula I or formula II, R³ is1-methoxy-2-methylpropan-2-yl.

In certain embodiments of formula I or formula II, R³ istetrahydro-2H-1,1-dioxo-thiopyran-4-yl.

In certain embodiments of formula I or formula II, R³ is3-fluoro-1-(oxetan-3-yl)piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-methoxypropan-2-yl.

In certain embodiments of formula I or formula II, R³ is1-(2,2,2-trifluoroethyl)azetidin-3-yl).

In certain embodiments of formula I or formula II, R³ is1-(oxetan-3-yl)pyrrolidin-3-yl.

In certain embodiments of formula I or formula II, R³ is1-isopropylazetidin-3-yl.

In certain embodiments of formula I or formula II, R³ is3-fluoro-1-methylpiperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-ethyl-3-fluoropiperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-methylpyrrolidin-3-yl.

In certain embodiments of formula I or formula II, R³ is2-methoxyethyl)piperidin-4-yl).

In certain embodiments of formula I or formula II, R³ is1-methyl-1-(methylamino-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ is2-methyl-2-morpholino-propyl.

In certain embodiments of formula I or formula II, R³ is4,4-difluorocyclohexyl.

In certain embodiments of formula I or formula II, R³ isdimethylamino-carbonyl-methyl.

In certain embodiments of formula I or formula II, R³ ismethylamino-carbonyl-methyl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1-(dimethylamino-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ ispyrrolidin-′-yl-carbonyl.

In certain embodiments of formula I or formula II, R³ is1-cyano-cyclopropyl.

In certain embodiments of formula I or formula II, R³ is1-(pyrrolidin-′-yl-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(dimethylamino-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(methoxy-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(tert-butylamino-carbonyl)-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(2,2,2-trifluoroethyllamino-carbonyl)-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(ethylamino-carbonyl)-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-(ethylamino-carbonyl)-cyclobutyl.

In certain embodiments of formula I or formula II, R³ is1-(isopropylamino-carbonyl)-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-cyano-cyclobutyl.

In certain embodiments of formula I or formula II, R³ isdimethyl-[1,3]dioxan-5-yl.

In certain embodiments of formula I or formula II, R³ is2-methoxy-2-methyl-propan-1-yl.

In certain embodiments of formula I or formula II, R³ is2-methoxy-1-methyl-ethyl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1-(methoxy-carbonyl)-ethyl.

In certain embodiments of formula I or formula II, R³ is1-oxetan-3-yl-pyrrolidin-3-yl.

In certain embodiments of formula I or formula II, R³ isisopropylsulfonyl.

In certain embodiments of formula I or formula II, R³ isbutane-2-sulfonyl.

In certain embodiments of formula I or formula II, R³ is1-(2-fluoroethyl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is3-fluoro-1-methyl-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-ethyl-3-fluoro-piperidin-4-yl. In certain embodiments of formula I orformula II, R³ is pyridin-3-ylmethyl.

In certain embodiments of formula I or formula II, R³ is6-methyl-pyridin-2-ylmethyl.

In certain embodiments of formula I or formula II, R³ is2-(morpholin-1-yl)-1,1,dimethyl-ethyl.

In certain embodiments of formula I or formula II, R³ ispyrimdin-2-yl-methyl.

In certain embodiments of formula I or formula II, R³ is3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ is1-(oxetan-3-yl)-piperidin-3-yl.

In certain embodiments of formula I or formula II, R³ is1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl.

In certain embodiments of formula I or formula II, R³ ispyridazin-3-ylmethyl.

In certain embodiments of formula I or formula II, R³ is piperidin-3-yl.

In certain embodiments of formula I or formula II, R³ ispyrazin-2-ylmethyl.

In certain embodiments of formula I or formula II, R³ is2-hydroxy-3-methyl-butan-1-yl.

In certain embodiments of formula I or formula II, R³ is1-([1,3]dioxolan-2-ylmethyl)-pyrrolidin-3-yl.

In certain embodiments of formula I or formula II, R³ ispyrimidin-4-ylmethyl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1H-pyrazol-3-ylmethyl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl.

In certain embodiments of formula I or formula II, R³ is3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl.

In certain embodiments of formula I or formula II, R³ is2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl.

In certain embodiments of formula I or formula II, R³ is2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl.

In certain embodiments of formula I or formula II, R³ is2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl.

In certain embodiments of formula I or formula II, R³ is2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl.

In certain embodiments of formula I or formula II, R³ is2-(1-methyl-1H-pyrazol-5-yl.

In certain embodiments of formula I or formula II, R³ is2-(4H-1,2,4-triazol-3-yl)propan-2-yl.

In certain embodiments of formula I or formula II, R³ is1-methyl-1H-pyrazole-4-yl.

In embodiments of formula I or formula II wherein R³ is aryl, such arylmay be unsubstituted phenyl or phenyl substituted one or more times withR⁸, or in certain embodiments, once, twice or three times with a groupor groups independently selected from C₁₋₆alkyl, halo, halo-C₁₋₆alkyl,C₁₋₆alkoxy, hydroxy or cyano.

In embodiments of formula I or formula II wherein R³ is heteroaryl orheteroaryl-C₁₋₆alkyl, such heteroaryl moiety may be pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, isoxazolyl, isothiazolyl, triazolyl, oxadiaolyl,thiadiazolyl or tetrazolyl, each being unsubstituted or substituted onceor twice with R⁸, or in certain embodiments, substituted once or twicewith C₁₋₆alkyl.

In embodiments of formula I or formula II wherein R³ is heteroaryl orheteroaryl-C₁₋₆alkyl, such heteroaryl moiety may be pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or oxadiaolyleach being unsubstituted or substituted once or twice with R⁸, or incertain embodiments, substituted once or twice with C₁₋₆alkyl.

In embodiments of formula I or formula II wherein R³ is heteroaryl orheteroaryl-C₁₋₆alkyl, such heteroaryl moiety may be pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, each being unsubstituted or substituted one or more timeswith R⁸

In embodiments of formula I or formula II wherein R³ is heterocyclyl,such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl, each being unsubstituted or substituted one ormore times with R⁷.

In embodiments of formula I or formula II wherein R³ isheterocyclyl-C₁₋₆alkyl, such heterocyclyl moiety may be piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl, each being unsubstituted or substituted one ormore times with R⁷.

In certain embodiments of formula I or formula II, R³ is —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, Y is a bond.

In certain embodiments of formula I or formula II, Y is C₂₋₆alkylene.

In certain embodiments of formula I or formula II, Y is isopropylidine.

In certain embodiments of formula I or formula II, Y is methylene.

In certain embodiments of formula I or formula II, Y is ethylene.

In certain embodiments of formula I or formula II, Y is —C(CH₃)₂—.

In certain embodiments of formula I or formula II, Y is —CH₂—.

In certain embodiments of formula I or formula II, Y is —CH(CH₃)—.

In certain embodiments of formula I or formula II, Y is —CH₂—C(CH₃)₂—.

In certain embodiments of formula I or formula II, Y is —C(CH₃)₂—CH₂—.

In certain embodiments of formula I or formula II, R^(d) is C₁₋₆alkyl,C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R^(d) is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R^(d) is amino

In certain embodiments of formula I or formula II, R^(d) ishalo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) ishydroxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) iscyano-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) isC₁₋₆alkylsulfonylC₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) isamino-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R^(d) isC₃₋₆cycloalkyl optionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R^(d) isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R^(d) is heterocyclyloptionally substituted one or more times with R⁷.

In certain embodiments of formula I or formula II, R^(d) isheterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion is optionallysubstituted one or more times with R⁷.

In certain embodiments of formula I or formula II, R^(d) is1-methyl-cyclopropyl; methylamino; dimethylamino; pyrrolidin-1-yl;methoxy; cyclopropyl-methyl; ethyl; 2,2,2-trifluoro-ethyl; tert-butyl;or isopropyl.

In certain embodiments of formula I or formula II, R^(d) is1-methyl-cyclopropyl.

In certain embodiments of formula I or formula II, R^(d) is methylamino.

In certain embodiments of formula I or formula II, R^(d) isdimethylamino

In certain embodiments of formula I or formula II, R^(d) ispyrrolidin-1-yl.

In certain embodiments of formula I or formula II, R^(d) is methoxy.

In certain embodiments of formula I or formula II, R^(d) iscyclopropyl-methyl.

In certain embodiments of formula I or formula II, R^(d) is ethyl.

In certain embodiments of formula I or formula II, R^(d) is2,2,2-trifluoro-ethyl.

In certain embodiments of formula I or formula II, R^(d) is tert-butyl.

In certain embodiments of formula I or formula II, R^(d) is isopropyl.

In embodiments of formula I or formula II wherein R^(d) is heterocyclylor heterocyclyl-C₁₋₆alkyl, such heterocyclyl may be piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl,tetrahydrofuranyl or oxetanyl, each optionally substituted one or moretimes, or one or two times, with R⁷ as defined herein.

In embodiments of formula I or formula II wherein R^(d) is heterocyclyl,such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl, each being unsubstituted or substituted one ormore times with R⁷.

In embodiments of formula I or formula II wherein R^(d) isheterocyclyl-C₁₋₆alkyl, such heterocyclyl moiety may be piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl, each being unsubstituted or substituted one ormore times with R⁷.

In certain embodiments of formula I or formula II, R⁴ is: hydrogen;C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R⁴ is: C₁₋₆alkyl;halo; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R⁴ is: hydrogen;C₁₋₆alkyl; halo; C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; or —C(O)—R^(c) wherein R^(c) isC₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R⁴ is: hydrogen;C₁₋₆alkyl; halo; or C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is hydrogen orC₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is hydrogen.

In certain embodiments of formula I or formula II, R⁴ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is halo.

In certain embodiments of formula I or formula II, R⁴ is cyano.

In certain embodiments of formula I or formula II, R⁴ is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ ishydroxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is hydrogen ormethyl.

In certain embodiments of formula I or formula II, R⁴ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁴ is —C(O)—R^(c)wherein R^(c) is C₁₋₆alkyl, C₁₋₆alkoxy, amino, or heterocyclyl.

In certain embodiments of formula I or formula II, R⁴ is —C(O)—R^(c)wherein R^(c) is heterocyclyl.

In embodiments of formula I or formula II wherein R^(c) is heterocyclyl,such heterocyclyl may be pyrrolidinyl, piperidinyl, piperazinyl ormorpholinyl.

In embodiments of formula I or formula II wherein R^(c) is heterocyclyl,such heterocyclyl may be piperidinyl, piperazinyl or morpholinyl.

In certain embodiments of formula I or formula II, R⁴ is: hydrogen;methyl; isopropyl; cyclopropyl; chloro; or morpholin-4-yl-carbonyl.

In certain embodiments of formula I or formula II, R⁴ is: hydrogen;methyl; isopropyl; cyclopropyl; or chloro.

In certain embodiments of formula I or formula II, R⁴ is hydrogen.

In certain embodiments of formula I or formula II, R⁴ is methyl.

In certain embodiments of formula I or formula II, R⁴ is isopropyl.

In certain embodiments of formula I or formula II, R⁴ is cyclopropyl.

In certain embodiments of formula I or formula II, R⁴ is chloro.

In certain embodiments of formula I or formula II, R⁴ ismorpholin-4-yl-carbonyl.

In certain embodiments of formula I or formula II, R⁴ is 2-fluoro-ethyl.

In certain embodiments of formula I or formula II, R⁴ is C₃₋₆cycloalkyloptionally substituted one or more times, or one or two times, with R⁶.

In certain embodiments of formula I or formula II, R⁴ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times, or one or two times, with R⁶.

In certain embodiments of formula I or formula II, R⁴ is —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, or R³ and R⁴ togetherwith the atoms to which they are attached may form a 5- or 6-memberedring that optionally includes a heteroatom selected from O, N and S.

In certain embodiments of formula I or formula II, R⁵ is hydrogen.

In certain embodiments of formula I or formula II, R⁵ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁵ is methyl.

In certain embodiments of formula I or formula II, each R⁶ isindependently C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; cyano; or halo.

In certain embodiments of formula I or formula II, R⁶ is C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; or halo.

In certain embodiments of formula I or formula II, R⁶ is C₁₋₆alkyl;halo-C₁₋₆alkyl; or halo.

In certain embodiments of formula I or formula II, R⁶ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁶ is halo-C₁₋₆alkyl.In certain embodiments of formula I or formula II, R⁶ is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R⁶ is cyano.

In certain embodiments of formula I or formula II, R⁶ is halo.

In certain embodiments of formula I or formula II, R⁶ is Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, R⁶ is oxo.

In certain embodiments of formula I or formula II, each R⁷ isindependently C₁₋₆alkyl; halo-C₁₋₆alkyl; halo; C₁₋₆alkylsulfonyl;C₁₋₆alkoxy-C₁₋₆alkyl; cyano; heterocyclyl; or C₃₋₆cycloalkylsulfonylwherein the C₃₋₆cycloalkyl portion is optionally substituted one or moretimes with R⁶.

In certain embodiments of formula I or formula II, R⁷ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is halo.

In certain embodiments of formula I or formula II, R⁷ isC₁₋₆alkylsulfonyl.

In certain embodiments of formula I or formula II, R⁷ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is cyano.

In certain embodiments of formula I or formula II, R⁷ is —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, R⁷ is heterocyclyl.

In certain embodiments of formula I or formula II, R⁷ isC₃₋₆cycloalkylsulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R⁷ is oxo.

In certain embodiments of formula I or formula II, R⁷ is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R⁷ isheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is C₃₋₆cycloalkyl.

In certain embodiments of formula I or formula II, R⁷ isC₃₋₆cycloalkyl-C₁₋₆alkyl.

In embodiments of formula I or formula II wherein R⁷ is heterocyclyl,such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl.

In embodiments of formula I or formula II wherein R⁷ isheterocyclyl-C₁₋₆alkyl, such heterocyclyl moiety may be piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl.

In certain embodiments of formula I or formula II, each R⁸ isindependently oxo; C₁₋₆alkyl; halo-C₁₋₆alkyl; halo; C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkyl; cyano; C₃₋₆cycloalkyl optionally substituted oneor more times with R⁶, C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted one or more times withR⁶, or C₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R⁸ is oxo. In certainembodiments of formula I or formula II, R⁷ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is halo-C₁₋₆alkylIn certain embodiments of formula I or formula II, R⁷ is halo. Incertain embodiments of formula I or formula II, R⁷ is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R⁷ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁷ is cyano.

In certain embodiments of formula I or formula II, R⁷ is hetoeryclyl.

In certain embodiments of formula I or formula II, R⁷ is —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, R⁷ is C₃₋₆cycloalkyloptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R⁷ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R⁷ isC₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I or formula II, R⁸ is oxo.

In certain embodiments of formula I or formula II, R⁸ is C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁸ is halo-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁸ is halo.

In certain embodiments of formula I or formula II, R⁸ isC₁₋₆alkyl-sulfonyl.

In certain embodiments of formula I or formula II, R⁸ is C₁₋₆alkoxy.

In certain embodiments of formula I or formula II, R⁸ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁸ is cyano;hetoeryclyl.

In certain embodiments of formula I or formula II, R⁸ isheterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I or formula II, R⁸ is —Y—C(O)—R^(d).

In certain embodiments of formula I or formula II, R⁸ is C₃₋₆cycloalkyl.

In certain embodiments of formula I or formula II, R⁸ isC₃₋₆cycloalkyl-C₁₋₆alkyl-C₃₋₆cycloalkyl-sulfonyl.

In embodiments of formula I or formula II wherein R⁸ is heterocyclyl,such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl.

In embodiments of formula I or formula II wherein R⁸ isheterocyclyl-C₁₋₆alkyl, such heterocyclyl moiety may be piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl,tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl ortetrahydrothiopyranyl.

In certain embodiments of the invention, compounds of formulas III, IVand V are provided:

wherein X, R¹, R, R², R³, R⁴ and R⁵ are as defined herein.

In certain embodiments of the invention, the subject compounds are offormula III.

In certain embodiments of the invention, the subject compounds are offormula IV.

In certain embodiments of the invention, the subject compounds are offormula V.

Where any of R¹, R², R′ R⁴, R⁵, R⁶, R⁷, R⁸ R^(a), R^(b), R^(c) and R^(d)is alkyl or contains an alkyl moiety, such alkyl may be lower alkyl,i.e. C₁-C₆alkyl, and in many embodiments may be C₁-C₄alkyl.

The invention also provides a method for treating a disease or conditionmediated by or otherwise associated with the LRRK2 receptor, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The disease may be a neurodegenerative disease such as Parkinson'sdisease, Huntington's disease or Lewie body dementia.

The disease may be a CNS disorder such as Alzheimer's disease or L-Dopainduced dyskinesia.

The disease may be a cancer or proliferative disorder such as kidney,breast, prostate, blood, papillary or lung cancer, acute myelogenousleukemia, or multiple myeloma.

The disease may be an inflammatory disease such as leprosy, Crohn'sdisease, amyotrophic lateral sclerosis, rheumatoid arthritis, orankylosing spondylytis.

The invention also provides a method for enhancing cognitive memory, themethod comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

Representative compounds in accordance with the methods of the inventionare shown in the experimental examples below.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein may beconducted under an inert atmosphere at atmospheric pressure at areaction temperature range of from about −78° C. to about 150° C., forexample, from about 0° C. to about 125° C., or conveniently at aboutroom (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula I, wherein X, R¹, R², R³, R⁴ and R⁵ are asdefined herein.

In step 1 of Scheme A, dichloropyrimidine compound a is reacted withreagent b to afford pyrimidine compound c. The reaction of step 1 maytake place under polar solvent conditions. In embodiments of theinvention where X is —O— (reagent b is an alcohol), the reaction of step1 may be carried out in the presence of base.

Following step 1, one of steps 2a, 2b and 2c is carried out. In step 2a,pyrimidine compound c undergoes reaction with 4-amino-pyrazole compoundd1 to provide an aminopyrimidine compound of formula III. In step 2b,pyrimidine compound c is reacted with 5-amino-pyrazole compound d2 toafford an aminopyrimidine compound of formula IV. In step 2c, pyrimidinecompound c is treated with 3-amino-pyrazole compound d3 to yield anaminopyrimidine compound of formula V. The reaction of steps 2a-2c maytake place in polar protic solvent and in the presence of acid such asHCl.

Many variations on the procedure of Scheme A are possible and willsuggest themselves to those skilled in the art. Specific details forproducing compounds of the invention are described in the Examplesbelow.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, for example 1-100 mg daily, and insome embodiments 1-30 mg daily, depending upon numerous factors such asthe severity of the disease to be treated, the age and relative healthof the subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. A particular manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets may contain from aboutone (1) to about seventy (70) percent of the active compound. Suitablecarriers include but are not limited to magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations may be in unit dosage forms. In suchform, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

Utility

The compounds of the invention are useful for treatment ofLRRK2-mediated diseases or conditions, including neurodegenerativediseases such as Parkinson's disease, Lewy body dementia andHuntington's disease, and for enhancemenent of cognitive memorygenerally in subjects in need thereof.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

Abbreviations

-   AcOH Acetic acid-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   Atm. Atmosphere-   (BOC)₂O di-tent-Butyl dicarbonate-   dba tris(dibenzylideneacetone)-   DCM Dichloromethane/Methylene chloride-   DIAD Diisopropyl azodicarboxylate-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   DPPF 1,1′-Bis(diphenylphosphino)ferrocene-   Et₂O Diethyl ether-   EtOH Ethanol/Ethyl alcohol-   EtOAc Ethyl acetate-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole-   HPLC High pressure liquid chromatography-   HPLC Reverse phase high pressure liquid chromatography-   i-PrOH Isopropanol/isopropyl alcohol-   LCMS Liquid Chromatograph/Mass Spectroscopy-   MeOH Methanol/Methyl alcohol-   MW Microwaves-   NBS N-Bromosuccinimide-   NMP 1-Methyl-2-pyrrolidinone-   PSI Pound per square inch-   RT Room temperature-   SFC Supercritical fluid chromatography-   TBDMS tert-Butyldimethylsilyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin layer chromatography-   Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Liquid Chromatography-Mass Spectrometry Method A

LC-MS was performed on an Agilent 1200 Series LC coupled to an Agilent6140 quadrupole mass spectrometer using an Agilent SD-C18 column (1.8μm, 2.1×30 mm) with a linear gradient of 3-95% acetonitrile/water (with0.05% trifluoroacetic acid in each mobile phase) within 8.5 minutes andheld at 95% for 2.5 minutes.

Liquid Chromatography-Mass Spectrometry Method B

LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996Diode Array Detector coupled to a Micromass ZQ, single quadrapole massspectrometer using a Phenomenex Luna C18 (2) column (5 um, 100×4.6 mmplus guard cartridge) with a linear gradient of 5-95% acetonitrile/water(with 0.1% formic acid in each mobile phase) within 3.5 minutes and heldat 95% for 2.0 minutes.

Liquid Chromatography-Mass Spectrometry Method C

LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996Diode Array Detector coupled to a Micromass ZQ, single quadrapole massspectrometer using a Waters Xterra MS C18 column (5 um, 100×4.6 mm plusguard cartridge) being initially held at 5% acetonitrile/water (with 10mM ammonium bicarbonate in the aqueous mobile phase) for 0.5 minutes,followed by a linear gradient of 5-95% within 3.5 minutes and then heldat 95% for 1.5 minutes.

Analytical Methods

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using aBruker instrument operating at 400 or 500 MHz using the stated solventat around room temperature unless otherwise stated. In all cases, NMRdata were consistent with the proposed structures. Characteristicchemical shifts (δ) are given in parts-per-million using conventionalabbreviations for designation of major peaks: e.g. s, singlet; d,doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet oftriplets; br, broad. Where thin layer chromatography (TLC) has been usedit refers to silica gel TLC using silica gel MK6F 60 Å plates, R_(f) isthe distance travelled by the compound divided by the distance travelledby the solvent on a TLC plate. Flash chromatography refers to silica gelchromatography and is carried out using an SP4 or an Isolara 4 MPLCsystem (manufactured by Biotage); pre-packed silica gel cartridges(supplied by Biotage); or using conventional glass columnchromatography.

Compound Preparation

Where the preparation of starting materials is not described, these arecommercially available, known in the literature, or readily obtainableby those skilled in the art using standard procedures. Where it isstated that compounds were prepared analogously to earlier examples orintermediates, it will be appreciated by the skilled person that thereaction time, number of equivalents of reagents and temperature can bemodified for each specific reaction and that it may be necessary ordesirable to employ different work-up or purification techniques. Wherereactions are carried out using microwave irradiation, the microwaveused is an Initiator 60 supplied by Biotage. The actual power suppliedvaries during the course of the reaction in order to maintain a constanttemperature.

Compounds made in the following examples are summarized in the Tablesbelow, which shows affinity values for LRRK2 (Ki, micromolar) forrepresentative compounds together with LCMS method (M), LC retentiontime (RT) in minutes, and Mass Spec m/z values (molecular weight).

Intermediate 1 2,5-Dichloro-4-methoxypyrimidine

To a 250 mL round bottom flask equipped with a stir bar was added2,4,5-trichloro-pyrimidine (1 g), and diethyl ether (15 mL). The mixturewas cooled to 0° C. in an ice bath and then 1 equivalent of sodiummethoxide in methanol (prepared from reacting 120 mg of sodium with 4 mLof methanol at room temperature) was slowly added. The reaction wasstirred over night at room temperature and checked by LCMS. The whiteprecipitate was filtered and the solid washed with cold methanol. Afterdrying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidine was obtained andthis material was used without further purification. ¹H-NMR (DMSO): δ8.61 (s, 1H), 4.05 (s, 3H).

Intermediate 2 2,5-Dichloro-N-methylpyrimidin-4-amine

To a cooled (0° C.) solution of 2,4,5-trichloropyrimidine (2.0 g, 11mmol) in methanol (30 mL) was added dropwise a 2 M solution ofmethylamine in methanol (6.3 mL). The reaction was allowed to warm toroom temperature and stirred overnight. The reaction was thenconcentrated and redissolved in DCM. The solution was washed with sat.NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (0-40% EtOAc in heptane)to give 2,5-dichloro-N-methylpyrimidin-4-amine (0.9 g, 50%). ¹H-NMR(DMSO): δ 8.13 (s, 1H), 7.89 (s, 1H), 2.86 (d, J=4.5, 3H).

Intermediate 3 5-Bromo-2-chloro-N-methylpyrimidin-4-amine

To a cooled (0° C.) solution of 5-bromo-2,4-dichloropyrimidine (5.0 g,22 mmol) in methanol (42 mL) was added dropwise a 33 wt % solution ofmethylamine in ethanol (3.3 mL). The reaction was allowed to warm toroom temperature. The reaction was then concentrated. The crude productwas purified by column chromatography (0-10% methanol in DCM) to give5-bromo-2-chloro-N-methylpyrimidin-4-amine (1.8 g, 39%). ¹H-NMR (DMSO):δ 8.22 (s, 1H), 7.75 (s, 1H), 2.85 (d, J=3.9, 3H).

Intermediate 4 5-Bromo-2-chloro-4-methoxypyrimidine

To a cooled (−78° C.) solution of 5-bromo-2,4-dichloropyrimidine (1.7 g,7.3 mmol) in THF (30 mL) was added dropwise a 25 wt % solution ofmethylamine in ethanol (1.7 mL). The reaction was allowed to warm to 0°C. and stirred for 1 h. The reaction was then concentrated andre-dissolved in EtOAc. The solution was washed with brine, dried overNa₂SO₄, filtered and concentrated to give5-bromo-2-chloro-4-methoxypyrimidine (1.25 g, 76%). ¹H-NMR (CDCl₃): δ8.43 (s, 1H), 4.10 (s, 3H).

Intermediate 5 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

To a 250 mL round bottom flask equipped with a stir bar was added5-fluoro-2,4-dichloro-pyrimidine (9 g), methanol (40 mL) and 8Mmethylamine in ethanol (15 mL). The reaction heated up (mild exo-therm)and was allowed to stir at room temperature for 30 minutes. A check byTLC (1:1 EtOAc:heptane) and LCMS showed complete reaction. The reactionwas concentrated down to give 9.77 g crude material which was purifiedon a silica column running a gradient of 1% to 10% MeOH in DCM over 35minutes to give 2-chloro-5-fluoro-N-methylpyrimidin-4-amine (6.77 g).

Intermediate 6 2-Chloro-5-iodo-N-methylpyrimidin-4-amine

2-chloro-5-iodo-N-methylpyrimidin-4-amine was prepared following theprocedure of Intermediate 5 but using 2,4-dichloro-5-iodopyrimidine.¹H-NMR (DMSO): δ 8.26 (s, 1H), 5.47 (s, 1H), 3.07 (d, J=4.9, 3H).

Intermediate 7 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine

To a cooled (−10° C.) solution of2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol(100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solutionof methylamine in methanol (45 mL). The reaction was allowed to warm toroom temperature and stirred overnight. The reaction was thenconcentrated and re-dissolved in ethyl acetate. The solution was washedwith sat. NaHCO₃, brine, dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography (5-25% EtOAc inheptane) to give 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(8.6 g, 45%). ¹H-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).

Intermediate 82-chloro-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine

2-Chloro-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine was preparedaccording to the procedure described for intermediate 7 usingpyrrolidine.

Intermediate 9 2,5-Dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine

To a solution of tetrahydro-4-pyranol (0.36 g, 3.54 mmol) in DMF (5 mL)was added sodium hydride (60% dispersion, 0.17 g, 4.25 mmol). Theresulting mixture was added to a solution of 2,4,5-trichloropyrimidine(650 mg, 3.5 mmol) in THF at 0° C. The combined mixture was then allowedto warm to room temperature. To the reaction was then added water andthe product was extracted with a 1:1 EtOAc-Heptane mixture. The extractwas then dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by column chromatrography (0-30% EtOAc in heptane) to give2,5-dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine. ¹H-NMR (CDCl₃):δ 8.33 (s, 1H), 5.42 (m, 1H), 4.09-3.90 (m, 2H), 3.65 (m, 2H), 2.19-1.99(m, 2H), 1.87 (m, 2H).

Additional intermediates prepared using similar methods as describedabove are listed in Table 1 below:

TABLE 1 10 2-chloro-N-ethyl-5- (trifluoromethyl)pyrimidin- 4-amine

11 2-chloro-N-(2,2- difluoroethyl)-5- (trifluoromethyl)pyrimidin-4-amine

12 2-chloro-N-((tetrahydro- 2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrimidin- 4-amine

13 2,5-dichloro-4- ethoxypyrimidine

14 2-chloro-4-(2,2,2- trifluoroethoxy)-5- (trifluoromethyl)pyrimidine

15 2-chloro-4-(2,2- difluoroethoxy)-5- (trifluoromethyl)pyrimidine

16 2,5-dichloro-4-(2,2- difluoroethoxy)pyrimidine

17 2,5-dichloro-4-(oxetan- 3-yloxy)pyrimidine

18 2-chloro-N-cyclopropyl-5- (trifluoromethyl)pyrimidin- 4-amine

Intermediates 19 and 20 5-Methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine

Step 1 5-Methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole

To a mixture of 3-methyl-4-nitro-pyrazole (0.80 g, 6.3 mmol), cesiumcarbonate (4.1 g, 12 mmol) in DMF (10 mL) was added 3-iodo-oxetane (3.47g, 19 mmol). The mixture was stirred at 100° C. for 3 h. The reactionwas diluted with water and extracted with ethyl acetate (3×). Thecombined extracts were washed with brine, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by columnchromatrography (20-100% EtOAc-heptane) to give a mixture of5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (0.85 g, 74%).

Step 2 5-Methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine

To a solution of 5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (0.137 g, 0.75 mmol) inethanol (2 mL) was added Pd—C (10 wt %, 0.10 g). The mixture was stirredunder a hydrogen atmosphere for 24 hours. The reaction was filteredthrough Celite® and concentrated to give a mixture of5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine (83 mg, 73%), which wereused together in the following Examples.

Additional intermediates made using the above procedure are shown inTable 2 below.

TABLE 2 21 1-(2-methoxyethyl)-5- methyl-1H-pyrazol-4-amine

22 1-(2-methoxyethyl)-3- methyl-1H-pyrazol-4-amine

23 1-(4-Amino-5-methyl- 1H-pyrazol-1-y1)-2- methylpropan-2-ol

24 1-(4-amino-3-methyl- 1H-pyrazol-1-yl)-2- methylpropan-2-ol

25 5-Methyl-1-(tetrahydro- 2H-pyran-4-yl)-1H- pyrazol-4-amine

26 3-Methyl-1-(tetrahydro- 2H-pyran-4-yl)-1H- pyrazol-4-amine

27 3-methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazol- 4-amine

28 5-methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazol- 4-amine

29 3-methyl-1-(tetrahydrofuran- 3-yl)-1H-pyrazol-4-amine

30 5-methyl-1-(tetrahydrofuran- 3-yl)-1H-pyrazol-4-amine

31 5-(4-amino-5-methyl- 1H-pyrazol-1-yl)-1- methylpiperidin-2-one

32 5-(4-amino-3-methyl- 1H-pyrazol-1-yl)-1- methylpiperidin-2-one

33 5-(4-amino-3-methyl- 1H-pyrazol-1-yl)piperidin- 2-one

34 5-(4-amino-5-methyl- 1H-pyrazol-1-yl)piperidin- 2-one

35 1-(1-methoxy-2- methylpropan-2-yl)-5-methyl- 1H-pyrazol-4-amine

36 1-(2-methoxy-2- methylpropyl)-5-methyl- 1H-pyrazol-4-amine

37 1-(2-methoxypropyl)-5- methyl-1H-pyrazol-4- amine

38 1-(1-methoxypropan-2-yl)- 5-methyl-1H-pyrazol-4- amine

39 3-methyl-1-(methylsulfonyl)- 1H-pyrazol-4-amine

40 1-(isopropylsulfonyl)-3- methyl-1H-pyrazol-4- amine

41 1-(cyclopropylsulfonyl)- 3-methyl-1H-pyrazol-4- amine

42 1-(isopropylsulfonyl)- 5-methyl-1H-pyrazol-4- amine

43 1-(cyclopropylsulfonyl)- 5-methyl-1H-pyrazol-4- amine

44 1-(sec-butylsulfonyl)- 5-methyl-1H-pyrazol-4- amine

45 1-(2,2-dimethyl-1,3- dioxan-5-yl)-5-methyl-1H- pyrazol-4-amine

46 5-methyl-1-((3- methyloxetan-3-yl)methyl)- 1H-pyrazol-4-amine

47 1-(2-fluoroethyl)-5- methyl-1H-pyrazol-4-amine

48 1-isopropy1-5-methyl- 1H-pyrazol-4-amine

Intermediate 49 5-Chloro-1-methyl-1H-pyrazol-4-amine

To a suspension of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1.0g, 6.2 mmol) in toluene (15 mL) was added triethylamine (1.7 mL, 12mmol) and diphenylphosphonic azide (2 mL, 9.3 mmol). The resultingsolution was stirred at room temperature for 30 minutes before heatingat 95° C. for 1 h. After cooling to room temperature, the reaction wasdiluted with water and extracted with ethyl acetate (3×). The combinedextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a yellow syrup. The crude product was purified bycolumn chromatography (0-50% EtOAc in heptane) to give5-chloro-1-methyl-1H-pyrazol-4-amine ¹H-NMR (CDCl₃): δ 7.90 (s, 1H),3.88 (s, 2H), 1.55 (s, 3H).

Intermediates 50 and 51(S)-3-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine and(S)-5-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine

Step 1: (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate

(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.0 g, 26.7 mmol) andEt₃N (8.0 g, 80.2 mmol) were dissolved in dichloromethane (50 mL). Themixture was stirred at 0° C. for 30 minutes, then methanesulfonylchloride (4.5 g, 40.1 mmol) was added dropwise. It was stirred at roomtemperature for 2 h and concentrated under reduced pressure. DCM (50 mL)and water (50 mL) were added. The organic phase was washed withsaturated NaHCO₃ (30 mL) and H₂O (2×30 mL), and concentrated to affordthe title compound as oil (6 g, 100%).

Step 2: (5)-tert-butyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and(5)-tert-butyl3-(5-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

A microwave vial equipped with a magnetic stirrer was charged with(R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (6.0 g,22.5 mmol), 5-methyl-4-nitro-1H-pyrazole (2 g, 15.1 mmol), K₂CO₃ (6.2 g,45.3 mmol) and DMF (50 mL). The reaction mixture was heated at 100° C.for 1 h under microwave irradiation. It was then filtered to get rid ofK₂CO₃ and the filtrate was concentrated. The residue was purified bysilica gel chromatography eluting with petroleum ether/ethyl acetate(2:1) to afford the mixture of the two title compounds as brown oil (5g, 100%). m/z (ES+APCI)⁺: [M+H]+ 241.

Alternatively, (5)-tert-butyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (049-3)and (S)-tert-butyl3-(5-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or relatedanalogs, such as tert-butyl3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate,can be prepared by the following procedure: To a solution of5-methyl-4-nitro-1H-pyrazole (0.99 g, 7.8 mmol), tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate (1.7 g, 7.8 mmol) andtriphenylphosphine (2.3 g, 8.5 mmol) in THF (8 mL) was added diisopropylazodicarboxylate (2 g, 9.3 mmol). The reaction was stirred at roomtemperature for 2 hours before being diluted with water and extractedwith EtOAc (4×). The organic extracts were washed with brine, dried oversodium sulfate, filtered and concentrated. The crude product waspurified by chromatography to give tert-butyl3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate(2.25 g, 88%).

Step 3: (S)-3-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazole and(S)-5-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazole

The mixture of (S)-tert-butyl3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and(5)-tert-butyl3-(5-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (5 g, 16.9mmol) was dissolved in dichloromethane (40 mL). CF₃COOH (10 mL) wasadded and the mixture was stirred at room temperature for overnight. Thesolvent was removed under reduced pressure to afford the mixture of thetwo title compounds as brown oil (4.0 g, 100%). m/z (ES+APCI)⁺: [M+H]+197.

Step 4:(S)-3-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole and(S)-5-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole

To the mixture of (S)-3-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazoleand (S)-5-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazole (4 g, 20.4mmol), oxetan-3-one (4.4 g, 61.2 mmol), and ZnCl₂ (8.3 g, 61.2 mmol) inMeOH (50 mL) was added NaBH₄ (3.8 g, 61.2 mmol). The mixture was stirredat 50° C. for 5 h. Then the solvent was removed in vacuum.Dichloromethane (100 mL) was added and the mixture was washed with water(2×50 mL). It was then concentrated in vacuo and purified by silica gelchromatography eluting with dichloromethane/methanol (25/1) to affordthe mixture of the two title compounds as yellow oil (3.8 g, 75%). m/z(ES+APCI)⁺: [M+H]+ 253.

Step 5:(S)-3-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine and(S)-5-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine

To the mixture of(S)-3-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole and(S)-5-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole (500mg, 1.98 mmol), and Zn (506 mg, 7.94 mmol) in methanol (20 mL) was addedTHF (20 mL) and NH₄Cl (841 mg, 15.9 mmol). The mixture was stirred at50° C. for 2 h. It was then concentrated and purified by reverse-phaseprep-HPLC to afford the mixture of the two title compounds as yellowsolid (200 mg, 45%). m/z (ES+APCI)⁺: [M+H]+ 223.

Additional intermediates made using the above procedure are shown inTable 3 below.

TABLE 3 52 5-methyl-1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-amine

53 3-methyl-1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-amine

54 3-methyl-1-(1-(oxetan- 3-yl)piperidin-4-yl)- 1H-pyrazol-4-amine

55 5-methyl-1-(1-(oxetan- 3-yl)piperidin-4-yl)- 1H-pyrazol-4-amine

56 1-(1-methylpiperidin- 4-yl)-1H-pyrazol-4- amine

57 3-methyl-1-(1- methylpiperidin-4-yl)- 1H-pyrazol-4-amine

58 1-(4-(4-amino-3- methyl-1H-pyrazol-1- yl)piperidin-1-yl)ethanone

59 1-(4-(4-amino-5- methyl-1H-pyrazol-1- yl)piperidin-1-yl)ethanone

60 (4-(4-amino-5- methyl-1H-pyrazol-1- yl)piperidin-1-yl)(cyclopropyl)methanone

61 (4-(4-amino-3- methyl-1H-pyrazol-1- yl)piperidin-1-yl)(cyclopropyl)methanone

62 (4-(4-amino-3-methyl- 1H-pyrazol-1- yl)piperidin-1-yl)(1-methylcyclo- propyl)methanone

63 3-methyl-1-(1- methylpiperidin-4-yl)-1H- pyrazol-4-amine

64 1-(3-fluoro-1- methylpiperidin-4-yl)- 3-methyl- 1H-pyrazol-4-amine

65 1-(1-ethyl-3- fluoropiperidin-4-yl)- 3-methyl- 1H-pyrazol-4-amine

66 3-methyl-1-(1- methylpyrrolidin-3-yl)- 1H-pyrazol-4-amine

Intermediates 67 and 683-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole compound with5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole

Step 1: 3-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazolecompound and 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole

A mixture of 3-methyl-4-nitro-1H-pyrazole (2.1 g, 17 mmol) and4-methylsulfonylphenylboronic acid (5.0 g, 25 mmol), copper (II) acetatemonohydrate (0.91 g, 5.0 mmol) and pyridine (0.5 g, 6.6 mmol) in DMF wasstirred at 95° C. under an oxygen atmosphere for 7 hours. The reactionwas diluted with water, extracted with EtOAc (3×). The combined extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The crude product was purified by flash chromatography togive a mixture of3-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole compound and5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole (1.3 g, 28%).

Step 2: 3-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazolecompound with 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole

A suspension of3-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole compound and5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole (0.57 g, 2.0mmol) and palladium on carbon (10 wt %, 0.2 g) in ethanol was stirredunder a hydrogen atmosphere at 55° C. for 18 hours. The reaction mixturewas filtered through celite and concentrated to give the title compoundsas a mixture of regioisomers (446 mg, 87%).

Additional intermediates made using the above procedure are shown inTable 4 below

TABLE 4 69 3-methyl-1-phenyl- 1H-pyrazol-4-amine

70 5-methyl-1-phenyl- 1H-pyrazol-4-amine

71 1-(4-chlorophenyl)-5- methyl-1H-pyrazol- 4-amine

72 1-(4-chlorophenyl)-3- methyl-1H-pyrazol- 4-amine

73 1-(4-fluorophenyl)-3- methyl-1H-pyrazol- 4-amine

74 1-(4-fluorophenyl)-5- methyl-1H-pyrazol- 4-amine

75 4-(4-amino-5-methyl- 1H-pyrazol-1- yl)benzonitrile

76 4-(4-amino-3-methyl- 1H-pyrazol-1- yl)benzonitrile

77 4-(4-amino-3-methyl- 1H-pyrazol-1-yl)-N,N- dimethylbenzamide

78 4-(4-amino-5-methyl- 1H-pyrazol-1-yl)-N,N- dimethylbenzamide

79 1-(3,5-difluorophenyl)- 5-methyl-1H-pyrazol- 4-amine

80 1-(3,5-difluorophenyl)- 3-methyl-1H-pyrazol- 4-amine

81 3-methyl-1-(pyridin- 2-yl)-1H-pyrazol- 4-amine

82 3-methyl-1-(pyrimidin- 5-yl)-1H-pyrazol- 4-amine

83 3-methyl-1-(2- methylpyridin-4-yl)- 1H-pyrazol-4-amine

84 5-methyl-1-(2- methylpyridin-4-yl)- 1H-pyrazol-4-amine

Intermediate 85 5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

Step 1: 5-Chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

To a solution of 4-nitro-1-tetrahydropyran-4-yl-pyrazole (1.32 g; 6.69mmol) in THF (15 mL) was added dropwise LHMDS (1 mol/L) in THF (2.0equiv.; 13.4 mmol) at −78° C. The reaction was stirred at −78° C. for 30minutes before the addition of hexachloroethane (2.4 g, 10 mmol) in THF(5 mL). The reaction was stirred at −78° C. before warming to roomtemperature. The reaction was diluted with sat. NaCl and extracted withEtOAc (3×). The combined extracts were washed with brine, dried oversodium sulfate, filtered and concentrated. The crude product waspurified by flash chromatography to give5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.98 g, 63%).

Step 2: 5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

To a solution of5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.4 g, 2mmol) in ethanol (10 mL) was added ammonium chloride (0.3 g, 5 mmol) andiron (0.3 g). The reaction was stirred at 90° C. for 30 minutes beforefiltered through celite and concentrated. The residue was titurated inEtOAc and filtered. The filtrated was concentrated to give the titlecompound (0.34 g, quant.)

Additional intermediates made using the above procedure are shown inTable 5 below.

TABLE 5 86 1-(4-amino-5-chloro-1H- pyrazol-1-yl)-2-methylpropan- 2-ol

87 methyl 2-(4-amino-5-chloro-1H- pyrazol-1-yl)-2- methylpropanoate

88 5-chloro-1-(oxetan-3-yl)-1H- pyrazol-4-amine

89 5-chloro-1-(cyclopropylmethyl)- 1H-pyrazol-4-amine

90 5-chloro-1-(1-methylpiperidin-4- yl)-1H-pyrazol-4-amine

91 5-chloro-1-(3-fluoro-1- methylpiperidin-4-yl)-1H- pyrazol-4-amine

92 5-chloro-1-ethyl-1H-pyrazol- 4-amine

93 5-chloro-1-(1-ethyl-3- fluoropiperidin-4-yl)-1H- pyrazol-4-amine

94 5-chloro-1-isopropyl-1H- pyrazol-4-amine

95 2-(4-amino-5-chloro-1H- pyrazol-1-yl)-2-methylpropan- 1-ol

Intermediates 96 3-Cyclopropyl-4-nitro-1H-pyrazole

Step 1: 3-cyclopropyl-1H-pyrazole

Ethynylcyclopropane (660 mg, 10 mmol) mixed with(diazomethyl)trimethylsilane (5 mL, 2M in hexane) in a 30 mL microwavetube was microwaved at 135° C. for 1 h. Then this reaction wasconcentrated in vacuo to give a light yellow oil product (1.02 g, 94%).This product was pure enough to be used to the next step reactionwithout further purification. MS: [M+H]⁺109.

Step 2: 3-Cyclopropyl-4-nitro-1H-pyrazole

To a cooling (0° C.) solution of 3-cyclopropyl-1H-pyrazole (1.5 g, 13.89mmol) in concentrated H₂SO₄ (20 mL, 98%) was added concentrated HNO₃ (20mL, 65%) over 2 min. The reaction mixture was stirred over 1 hr at thistemperature. It was then diluted with ice-water and extracted with EA(30 mL×4). The organic phase was combined and washed with saturatedsodium bicarbonate (50 mL). It was dried over Na₂SO₄ and concentrated invacuo to give a crude product (1.5 g, 70%). This crude product was pureenough to be delivered or used to the next step reaction. MS: [M+H]⁺154.¹H NMR (500 MHz, CDCl₃) δ 0.97 (m, 2H), 1.22 (m, 2H), 2.66 (m, 1H), 8.20(s, 1H), 8.38 (s, 1H).

Intermediates made using the above procedure are shown in Table 6 below

TABLE 6  97 5-isopropyl-4-nitro-1H-pyrazole

 98 5-cyclobutyl-4-nitro-1H-pyrazole

 99 5-tert-butyl-4-nitro-1H-pyrazole

100 4-nitro-5-(trifluoromethyl)-1H-pyrazole

Example 1N²-(1-isopropyl-1H-pyrazol-4-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a microwave tube was added2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (112 mg, 0.53mmol), 1-isopropyl-1H-pyrazol-4-amine (55 mg, 0.44 mmol), cesiumcarbonate (0.287 g, 0.88 mmol), XPhos (21 mg, 0.044 mmol), Pd₂(dba)₃ (20mg, 0.02 mmol) and dioxane (2.5 mL). The tube was sealed and thereaction was irradiated in the microwave at 140° C. for 30 minutes. Thereaction mixture was then filtered and concentrated. The crude productwas purified by reverse phase HPLC to giveN²-(1-isopropyl-1H-pyrazol-4-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(22 mg, 16%). LCMS (Method A): [MH⁺]=301.1 at 3.2 min. ¹H-NMR (DMSO): δ9.43 (m, 2H), 8.08 (s, 1H), 7.89 (s, 1H), 7.54 (s, 1H), 6.96 (m, 2H),4.43 (m, 1H), 2.92 (d, J=8.0, 3H), 1.39 (d, J=6.6, 6H).

Compounds made using the above procedure are shown in Table 7 below,together with low resolution mass spectrometry (M+H), proton NMR, andLRRK2 K_(i) (micromolar) data for selected compounds determined from theassay described below.

TABLE 7 Name Structure ¹H NMR M + H⁺ K_(I)  2 N²-(1,5-dimethyl-1H-pyrazol-4-yl)- N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.87 (s, 1 H), 8.04 (s, 1 H), 7.64 (s, 1 H), 6.90 (s, 2H), 3.69 (s, 3 H), 2.84 (s, 3 H), 2.17 (s, 3 H). 287.0  3N⁴-methyl-N²-(1- (2- morpholinoethyl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.53 (s, 1 H), 8.08 (s, 1 H), 7.88 (s, 1 H), 7.55 (s, 1H), 7.04 (s, 1 H), 4.17 (t, J = 6.0, 2 H), 3.61-3.49 (m, 4 H), 2.96 (s,3 H), 2.67 (t, J = 6.4, 2 H), 2.39 (s, 3 H). 372.1 0.015  4N⁴-methyl-N²-(1- methyl-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.53 (s, 1 H), 8.08 (s, 1 H), 7.81 (s, 1 H), 7.53 (s, 1H), 7.06 (s, 1 H), 3.79 (s, 3 H), 2.95 (s, 3 H). 273.0 0.0097  55-chloro-N²-(1- isopropyl-1H- pyrazol-4-yl)-N⁴- methyl- pyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 9.00 (s, 1 H), 7.5 (s, 2 H), 7.47 (s, 1 H), 7.06 (s, 1H), 4.47- 4.32 (m, 1 H), 2.91 (s, 3 H), 1.38 (d, J = 6.6, 6 H). 267.0  6N⁴-methyl-N²-(1- methyl-1H- pyrazol-5-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.40 (s, 1 H), 8.14 (s, 1 H), 7.32 (s, 1 H), 7.13 (s, 1H), 6.23 (s, 1 H), 3.66 (s, 3 H), 2.84 (d, J = 3.8, 3 H). 273.0 0.016  7N⁴-methyl-N²-(1- methyl-1H- pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.69 (s, 1 H), 8.10 (s, 1 H), 7.53 (s, 1 H), 7.02 (s, 1H), 6.60 (s, 1 H), 3.73 (s, 3 H), 2.91 (s, 3 H). 273.0 0.018  8N²-(1,3-dimethyl- 1H-pyrazol-4-yl)- N⁴-methyl-5- (trifluoromethyl)pyrimidine-2,4- diaminc

¹H-NMR (DMSO): δ 8.86 (s, 1 H), 8.07 (s, 1 H), 7.79 (s, 1 H), 6.94 (s, 1H), 3.72 (s, 3 H), 2.88 (s, 3 H), 2.10 (s, 3 H). 287.0  95-Chloro-N-(1,5- dimethyl-1H- pyrazol-4-yl)-4- (tetrahydro-2H- pyran-4-yloxy)pyrimidin- 2-amine

¹H-NMR (DMSO): δ 8.78 (s, 1 H), 8.15 (s, 1 H), 7.44 (s, 1 H), 5.20 (s, 1H), 3.85 (m, 2 H), 3.69 (s, 3 H), 3.47 (m, 2 H), 2.15 (s, 3 H), 1.98 (s,2 H), 1.66 (m, 2 H). 324.1 0.039 10 N⁴-methyl-5- (trifluoromethyl)-N²-(1,3,5- trimethyl-1H- pyrazol-4- yl)pyrimidinc-2,4- diamine

¹H-NMR (DMSO): δ 8.39 (m, 1 H), 7.99 (s, 1 H), 6.79 (s, 1 H), 3.62 (s, 3H), 2.78 (m, 3 H), 2.03 (s, 3 H), 1.94 (s, 3 H). 301.1 0.096 115-Chloro-N-(1- isopropyl-1H- pyrazol-4-yl)-4- (tetrahydro-2H- pyran-4-yloxy)pyrimidin- 2-amine

¹H-NMR (DMSO): δ 9.49 (s, 1 H), 8.23 (s, 1 H), 7.80 (s, 1 H), 7.47 (s, 1H), 5.31 (m, 1 H), 4.45 (m, 1 H), 3.88 (m, 2 H), 3.53 (m, 2 H), 2.06 (m,2 H), 1.70 (m, 2 H), 1.40 (d, 6 H). 338.1 0.033 12 5-Chloro-N-(1,5-dimethyl-1H- pyrazol-4-yl)-4- methoxy- pyrimidin- 2-amine

¹H-NMR (DMSO): δ 8.82 (s, 1 H), 8.13 (s, 1 H), 7.48 (s, 1 H), 3.91 (s, 3H), 3.69 (s, 3 H), 2.15 (s, 3 H). 254.0 0.0091 13 N-(1,5-dimethyl-1H-pyrazol-4-yl)- 4-(pyrrolidin-1- yl)-5- (trifluoromethyl)pyrimidin-2-amine

¹H-NMR (DMSO): δ 8.88 (s, 1 H), 8.22 (s, 1 H), 7.61 (s, 1 H), 3.69 (s, 3H), 3.51 (s, 4 H), 2.17 (s, 3 H), 1.87 (s, 4 H). 327.1 0.012 14N²-(1-ethyl-5- methyl-1H- pyrazol-4-yl)-N⁴- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.90 (s, 1 H), 8.05 (s, 1 H), 7.67 (s, 1 H), 6.95 (s, 1H), 4.01 (m, 2 H), 2.82 (s, 3 H), 2.19 (s, 3 H), 1.27 (t, J = 7.2, 3 H).301.1 0.024 15 5-Chloro-N-(1,3- dimethyl-1H- pyrazol-4-yl)-4- methoxy-pyrimidin- 2-amine

¹H-NMR (DMSO): δ 8.87 (s, 1 H), 8.17 (s, 1 H), 7.77 (s, 1 H), 3.95 (s, 3H), 3.72 (s, 3 H), 2.09 (s, 3 H). 254.0 0.0144 16 N⁴-methyl-N²-(3-methyl-1-(oxetan- 3-yl)-1H-pyrazol- 4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.97 (s, 1 H), 8.08 (m, 2 H), 6.96 (s, 1 H), 5.44 (m, 1H), 4.85 (m, 4 H), 2.89 (d, J = 4.4, 3 H), 2.18 (s, 3 H). 329.1 17N²-(5-chloro-1- methyl-1H- pyrazol-4-yl)-N⁴- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.87 (s, 1 H), 8.07 (s, 1 H), 7.71 (s, 1 H), 6.98 (s, 1H), 3.77 (s, 3 H), 2.83 (s, 3 H). 307.0 18 5-Chloro-4- methoxy-N-(3-methyl-1-(oxetan- 3-yl)-1H-pyrazol- 4-yl)pyrimidin-2- amine

¹H-NMR (DMSO): δ 8.97 (s, 1 H), 8.19 (s, 1 H), 7.98 (s, 1 H), 5.46 (s, 1H), 4.85 (s, 4 H), 3.96 (s, 3 H), 2.18 (s, 3 H). 296.0 0.022 195-Chloro-4- methoxy-N-(1-(2- methoxyethyl)-3- methyl-1H- pyrazol-4-yl)pyrimidin-2- amine

¹H-NMR (DMSO): δ 8.81 (s, 1 H), 8.13 (s, 1 H), 7.53 (s, 1 H), 4.14 (t, J= 5.4, 2 H), 3.90 (s, 3 H), 3.63 (t, J = 5.4, 2 H), 3.21 (s, 3 H), 2.16(s, 3 H) 298.0 0.015 20 5-chloro-4- methoxy-N-(1-(2- methoxyethyl)-5-methyl-1H- pyrazol-4- yl)pyrimidin-2- amine

1H-NMR (DMSO): δ 8.90 (s, 1 H), 8.17 (s, 1 H), 7.83 (s, 1 H), 4.13 (t, J= 5.2, 2 H), 3.95 (s, 3 H), 3.63 (t, J = 5.3, 2 H), 3.22 (s, 3 H), 2.11s, 3 H). 298.0 0.019 21 5-Chloro-N-(5- chloro-1-methyl-1H-pyrazol-4-yl)- 4-methoxy- pyrimidin-2- amine

¹H-NMR (DMSO): δ 8.99 (s, 1 H), 8.18 (s, 1 H), 7.67 (s, 1 H), 3.91 (s, 3H), 3.78 (s, 3 H). 274.0 0.020 22 2-Methyl-1-(3- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)propan-2-ol

¹H-NMR (DMSO): δ 8.89 (s, 1 H), 8.07 (s, 1 H), 7.95 (s, 1 H), 6.93 (s, 1H), 4.60 (s, 1 H), 3.88 (s, 2 H), 2.87 (d, J = 4.1, 3 H), 2.13 (s, 3 H),1.05 (s, 6 H). 345.1 23 2-Methyl-1-(3- methyl-4-(4- (methylamino)-5-chloro-pyrimidin- 2-ylamino)-1H- pyrazol-1- yl)propan-2-ol

¹H-NMR (DMSO): δ 8.92 (s, 1 H), 8.18 (s, 1 H), 7.86 (s, 1 H), 4.61 (s, 1H), 3.94 (s, 3 H), 3.89 (s, 2 H), 2.12 (s, 3 H), 1.05 (s, 6 H). 312.10.027 24 N²-(1-(2- methoxyethyl)-3- methyl-1H- pyrazol-4-yl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.82 (s, 1 H), 8.04 (s, 1 H), 7.64 (s, 1 H), 6.88 (s, 1H), 4.13 (t, J = 5.4, 2 H), 3.63 (t, J = 5.4, 2 H), 3.21 (s, 3 H), 2.83(s, 3 H), 2.17 (s, 3 H) 331.1 0.019 25 N²-(1-(2- methoxyethyl)-5-methyl-1H- pyrazol-4-yl)-N⁴- methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 8.89 (s, 1 H), 8.07 (s, 1 H), 7.91 (s, 1 H), 6.94 (s, 1H), 4.12 (t, J = 5.2, 2 H), 3.63 (t, J = 5.3, 2 H), 3.22 (s, 3 H), 2.88(d, J = 4.4, 3 H), 2.12 (s, 3 H). 331.1 26 5-Chloro-N-(1-ethyl-3-methyl- 1H-pyrazol-4- yl)-4-methoxy- pyrimidin-2- amine

¹H-NMR (DMSO): δ 8.87 (s, 1 H), 8.17 (s, 1 H), 7.81 (s, 1 H), 4.01 (q, J= 7.3, 2 H), 3.95 (s, 3 H), 2.10 (s, 3 H), 1.32 (t, J = 7.3, 3 H). 268.00.013 27 5-Chloro-N⁴- methyl-N²-(3- methyl-1-(oxetan- 3-yl)-1H-pyrazol-4-yl)pyrimidine- 2,4-diamine

¹H-NMR (DMSO): δ 8.36 (s, 1 H), 7.97 (s, 1 H), 7.82 (s, 1 H), 7.01 (d, J= 4.5, 1 H), 5.43 (m, 1 H), 4.85 (m, 4 H), 2.88 (d, J = 4.6, 3 H), 2.17(s, 3 H). 295.0 0.0088 28 N²-(1-isopropyl-3- methyl-1H-pyrazol-4-yl)-N⁴- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.89 (s, 1 H), 8.07 (s, 1 H), 7.93 (s, 1 H), 6.95 (s, 1H), 4.34 (m, 1 H), 2.88 (d, J = 4.4, 3 H), 2.12 (s, 3 H), 1.37 (d, J =6.7, 6 H). 315.1 29 5-Chloro-N-(1- isopropyl-3- methyl-1H-pyrazol-4-yl)-4- methoxy- pyrimidin-2- amine

¹H-NMR (DMSO): δ 8.87 (s, 1 H), 8.17 (s, 1 H), 7.84 (s, 1 H), 4.36 (m, 1H), 3.95 (s, 3 H), 2.11 (s, 3 H), 1.37 (d, J = 6.7, 6 H). 282.1 0.022 305-Chloro-N²-(1,3- dimethyl-1H- pyrazol-4-yl)-N⁴- methylpyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 8.25 (s, 1 H), 7.80 (s, 1 H), 7.74 (s, 1 H), 6.98 (d, J= 4.5, 1 H), 3.70 (s, 3 H), 2.87 (d, J = 4.6, 3 H), 2.08 (s, 3 H). 253.031 5-Chloro-N²-(1- isopropyl-3- methyl-1H- pyrazol-4-yl)-N⁴-methylpyrimidine- 2,4-diamine

¹H-NMR (DMSO): δ 8.26 (s, 1 H), 7.83 (s, 1 H), 7.80 (s, 1 H), 6.98 (d, J= 4.3, 1 H), 4.33 (m, 1 H), 2.87 (d, J = 4.6, 3 H), 2.10 (s, 3 H), 1.36(d, J = 6.7, 7 H). 281.1 0.012 32 N⁴-methyl-N²-(3- methyl-1-(tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.90 (s, 1 H), 8.07 (s, 1 H), 7.96 (s, 1 H), 6.95 (s, 1H), 4.24 (s, 1 H), 3.93 (d, J = 10.9, 2 H), 3.44 (t, J = 12.5, 2 H),2.89 (d, J = 4.3, 3 H), 2.13 (s, 3 H), 1.92 (s, 4 H). 357.2 0.024 33N⁴-methyl-N²-(5- methyl-1- (tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.83 (s, 1 H), 8.04 (s, 1 H), 7.65 (s, 1 H), 6.89 (s, 1H), 4.33 (m, 1 H), 3.95 (m, 2 H), 3.47 (t, J = 11.2, 2 H), 2.84 (s, 3H), 2.21 (s, 3 H), 2.02 (m, 2 H), 1.82-1.67 (m, 2 H). 357.2 34N²-(2-Ethyl-2H- pyrazol-3-yl)-5- fluoro-N⁴-methyl- pyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 8.75 (s, 1 H), 7.78 (d, 1 H), 7.39 (s, 1 H), 7.30 (s, 1H), 3.17 (s, 1 H), 3.99 (q, 2 H), 2.82 (d, 3 H), 1.26 (t, 3 H). 237.1 355-Fluoro-N⁴- methyl-N²-(2- methyl-2H- pyrazol-3-yl)- pyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 8.77 (s, 1 H), 7.78 (s, 1 H), 7.37 (s, 1 H), 7.26 (s, 1H), 6.17 (s, 1 H), 3.64 (s, 3 H), 2.82 (d, 3 H). 223.1 0.267 365-Fluoro-N⁴- methyl-N⁴-(2- propyl-2H- pyrazol-3-yl)- pyrimidine-2,4-diamine

¹H-NMR (DMSO): δ 8.79 (s, 1 H), 7.78 (s, 1 H), 7.41 (s, 1 H), 7.29 (s, 1H), 6.19 (s, 1 H), 3.94 (t, 2 H), 2.82 (d, 3 H), 1.69 (m, 2 H), 0.80 (t,3 H). 251.0 37 N²-(2,5-Dimethyl- 2H-pyrazol-3-yl)- 5-fluoro-N⁴- methyl-pyrimidine- 2,4-diamine

237.0 38 N²-(3-isopropyl-1- methyl-1H- pyrazol-5-yl)-N⁴- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.36 (s, 1 H), 8.14 (s, 1 H), 7.13 (d, J = 5.2, 1 H),6.08 (s, 1 H), 3.59 (s, 3 H), 2.86 (d, J = 4.3, 3 H), 2.84-2.73 (m, 1H), 1.17 (d, J = 6.9, 6 H). 315 0.012 39 5-Chloro-N-(3- cyclopropyl-1-methyl-1H- pyrazol-5-yl)-4- methoxy- pyrimidin- 2-amine

¹H-NMR (CDCl₃): δ 8.11 (s, 1 H), 6.64 (s, 1 H), 5.94 (s, 1 H), 3.98 (s,3 H), 3.69 (s, 3 H), 1.93-1.84 (m, 1 H), 0.94-0.84 (m, 2 H), 0.76-0.68(m, 2 H). 280 0.059 40 N²-(3- Cyclopropyl- 1-methyl-1H-pyrazol-5-yl)-N⁴- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.35 (s, 1 H), 8.13 (s, 1 H), 7.13 (d, J = 5.2, 1 H),5.94 (s, 1 H), 3.56 (s, 3 H), 2.85 (d, J = 4.3, 3 H), 1.78 (tt, J = 8.4,J = 5.0, 1 H), 0.84-0.74 (m, 2 H), 0.63-0.55 (m, 2 H). 313 415-Chloro-N-(3- isopropyl-1- methyl-1H- pyrazol-5-yl)-4- methoxy-pyrimidin- 2-amine

¹H-NMR (CDCl₃): δ 8.12 (s, 1 H), 6.65 (s, 1 H), 6.11 (s, 1 H), 3.98 (s,3 H), 3.72 (s, 3 H), 2.98-2.88 (m, 1 H), 1.27 (d, J = 6.9, 6 H). 2820.070 42 5-Chloro-N²-(5- isopropyl-2- methyl-2H- pyrazol-3-yl)-N⁴-methyl- pyrimidine- 2,4-diamine

¹H-NMR (CDCl₃): δ 7.87 (s, 1 H), 6.44 (s, 1 H), 6.13 (s, 1 H), 5.29 (s,1 H), 3.71 (s, 3 H), 3.01 (d, J = 4.9, 3 H), 2.97-2.89 (m, 1 H), 1.27(d, J = 6.9, 6 H). 281 0.016 43 5-Chloro-4- methoxy-N- (1,3,5-trimethyl-1H- pyrazol-4- yl)pyrimidin-2- amine

¹H-NMR (CDCl₃): δ 8.04 (s, 1 H), 6.04 (s, 1 H), 3.93 (s, 3 H), 3.73 (s,3 H), 2.13 (d, J = 5.39, 6 H). 268 44 5-Chloro-N⁴- methyl-N²-(1,3,5-trimethyl-1H- pyrazol-4-yl)- pyrimidine-2,4- diamine

¹H-NMR (CDCl₃): δ 7.80 (s, 1 H), 5.94 (s, 1 H), 5.18 (s, 1 H), 3.72 (s,3 H), 2.97 (d, J = 4.9, 3 H), 2.14 (d, J = 2.9, 6 H). 267 455-Chloro-N²-(5- cyclopropyl-2- methyl-2H- pyrazol-3-yl)-N⁴- methyl-pyrimidine- 2,4-diamine

¹H-NMR (CDCl₃): δ 7.86 (s, 1 H), 6.41 (s, 1 H), 5.95 (s, 1 H), 5.29 (s,1 H), 3.69 (s, 3 H), 3.01 (d, J = 4.9, 3 H), 1.92-1.85 (m, 1 H),0.91-0.85 (m, 2 H), 0.73-0.68 (m, 2 H). 279 0.0134 46 N⁴-Methyl-N²-(5-methyl-1-oxetan- 3-yl-1H-pyrazol- 4-yl)-5- trifluoromethyl-pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.91 (s, 1 H), 8.05 (s, 1 H), 7.86 (s, 1 H), 6.94 (s, 1H), 5.53 (m, 1 H), 4.93 (m, 2 H), 4.90- 4.83 (m, 2 H), 2.85 (s, 3 H),2.14 (s, 3 H). 329 47 N²-(1-isopropyl- 1H-pyrazol-5-yl)- N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 9.27 (s, 1 H), 8.12 (s, 1 H), 7.38 (d, J = 1.8, 1 H),7.11 (d, J = 5.2, 1 H), 6.17 (s, 1 H), 4.54-4.46 (m, 1 H), 2.81 (d, J =4.3, 3 H), 1.32 (d, J = 6.6, 6 H). 301 0.112 48 5-Chloro-N-(1-ethyl-5-methyl- 1H-pyrazol-4- yl)-4-methoxy- pyrimidin- 2-amine

¹H-NMR (DMSO): δ 8.81 (s, 1 H), 8.14 (s, 1 H), 7.51 (s, 1 H), 4.02 (q, J= 7.1, 2 H), 3.91 (s, 3 H), 2.17 (s, 3 H), 1.28 (t, J = 7.1, 4 H). 268.149 5-Chloro-N²-(1- ethyl-5-methyl- 1H-pyrazol-4- yl)-N⁴-methyl-pyrimidine- 2,4-diamine

¹H-NMR (DMSO): δ 8.21 (s, 1 H), 7.76 (s, 1 H), 7.51 (s, 1 H), 6.94 (s, 1H), 4.0 (q, J = 7.1, 2 H), 2.83 (d, J = 3.7, 3 H), 2.15 (s, 3 H), 1.27(t, J = 7.2, 3 H). 267.1 50 N²-(1-ethyl-3- methyl-1H- pyrazol-4-yl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.88 (s, 1 H), 8.07 (s, 1 H), 7.89 (s, 1 H), 6.94 (s, 1H), 4.00 (q, J = 7.1, 2 H), 2.88 (d, J = 3.9, 3 H), 2.11 (s, 3 H), 1.32(t, J = 7.2, 3 H). 301.1 51 5-Chloro-N²-(1- ethyl-3-methyl-1H-pyrazol-4- yl)-N⁴-methyl- pyrimidine- 2,4-diamine

¹H-NMR (DMSO): δ 8.26 (s, 1 H), 7.80 (s, 2 H), 6.99 (s, 1 H), 3.98 (q, 2H), 2.86 (s, 3 H), 2.10 (s, 3 H), 1.32 (t, 3 H). 267.1 525-chloro-N²-(1- isopropyl-1H- pyrazol-5-yl)-N⁴- methyl- pyrimidine-2,4-diamine

53 5-chloro-N-(1- isopropyl-1H- pyrazol-5-yl)-4- methoxy- pyrimidin-2-amine

54 5-chloro-4- methoxy-N-(3- methyl-1- (methylsulfonyl)- 1H-pyrazol-4-yl)pyrimidin-2- amine

¹H NMR (400 MHz, DMSO) δ 9.44 (s, 1 H), 8.41 (s, 1 H), 8.34 (s, 1 H),4.01 (s, 3 H), 3.42 (s, 3 H), 2.32 (s, 3 H). 0.0078 55 N²-(1-ethyl-1H-pyrazol-3-yl)-N⁴- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

56 5-chloro-4- methoxy-N-(5- methyl-1-phenyl- 1H-pyrazol-4-yl)pyrimidin-2- amine

1H NMR (400 MHz, DMSO) δ 9.17 (s, 1 H), 8.57 (s, 1 H), 8.25 (s, 1 H),7.73 (d, J = 7.9, 2 H), 7.46 (t, J = 7.9, 2 H), 7.23 (t, J = 7.4, 1 H),4.01 (s, 3 H), 2.26 (s, 3 H). 316.1 0.027 57 N²-(1-isopropyl-1H-pyrazol-3-yl)- N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

 0.0025 58 N⁴-methyl-N²-(5- methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.06 (s, 1 H), 7.74 (s, 1 H),6.93 (s, 1 H), 5.01 (q, J = 9.2, 2 H), 2.82 (s, 3 H), 2.22 (s, 3 H).0.0036 59 N²-(1-(2,2- dimethyl-1,3- dioxan-5-yl)-3- methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

387 60 5-chloro-4- methoxy-N-(5- methyl-1-(4- (methylsulfonyl)phenyl)-1H- pyrazol-4- yl)pyrimidin-2- amine

0.015 61 N⁴-ethyl-N²-(1- methyl-1H- pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

0.0046 62 5-chloro-N-(1,5- dimethyl-1H- pyrazol-4-yl)-4- (oxetan-3-yloxy)pyrimidin- 2-amine

0.039 63 5-chloro-4-(2,2- difluoroethoxy)- N-(1,5-dimethyl-1H-pyrazol-4- yl)pyrimidin-2- amine

0.024 64 5-chloro-N-(1,5- dimethyl-1H- pyrazol-4-yl)-4- (2,2,2-trifluoroethoxy) pyrimidin-2- amine

0.0586 65 5-chloro-4- methoxy-N-(3- methyl-1- (tetrahydro-2H-pyran-4-yl)-1H- pyrazol-4- yl)pyrimidin-2- amine

1H NMR (400 MHz, DMSO) δ 8.82 (s, 1 H), 8.14 (s, 1 H), 7.57 (s, 1 H),4.41-4.26 (m, 1 H), 4.03-3.82 (m, 5 H), 3.47 (t, J = 11.3, 2 H), 2.20(s, 3 H), 2.01 (qd, J = 12.4, 4.5, 2 H), 1.76 (dd, J = 12.5, 2.1, 2 H).0.0029 66 (4-(4-(5-chloro-4- methoxy- pyrimidin- 2-ylamino)-3-methyl-1H- pyrazol-1- yl)piperidin-1- yl)(1- methylcyclo- propyl)methanone

1H NMR (400 MHz, DMSO) δ 8.82 (s, 1 H), 8.14 (s, 1 H), 7.58 (s, 1 H),4.36 (m, 3 H), 3.91 (s, 2 H), 3.01 (s, 2 H), 2.21 (s, 3 H), 1.87 (m, 4H), 0.80 (m, 2 H), 0.55 (m, 2 H). 0.066 67 (4-(4-(5-chloro-4- methoxy-pyrimidin- 2-ylamino)-5- methyl-1H- pyrazol-1- yl)piperidin-1- yl)(1-methylcyclo- propyl) methanone

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.17 (s, 1 H), 7.89 (s, 1 H),4.39-4.24 (m, 4 H), 2.96 (s, 2 H), 2.11 (s, 3 H), 2.01 (m, 3 H), 1.74(m, 3 H), 1.24 (s, 4 H), 0.81 (t, J = 5.1, 2 H), 0.54 (m, 2 H). 0.089 684-(4-(5-chloro-4- methoxy- pyrimidin- 2-ylamino)-3- methyl-1H-pyrazol-1- yl)benzonitrile

1H NMR (400 MHz, DMSO) δ 9.29 (s, 1 H), 8.71 (s, 1 H), 8.27 (s, 1 H),7.98-7.86 (m, 4 H), 4.02 (s, 3 H), 2.29 (s, 3 H). 0.0024 69 5-chloro-4-methoxy-N-(3- methyl-1-(3- methylpyridin-4- yl)-1H-pyrazol-4-yl)pyrimidin-2- amine

1H NMR (400 MHz, DMSO) δ 9.25 (s, 1 H), 8.53 (s, 1 H), 8.46 (d, J = 5.4,1 H), 8.43 (s, 1 H), 8.26 (s, 1 H), 7.47 (d, J = 5.4, 1 H), 4.01 (s, 3H), 2.45 (s, 3 H), 2.29 (s, 3 H). 0.055 70 5-chloro-N-(1- (cyclopropyl-sulfonyl)- 5-methyl-1H- pyrazol-4-yl)-4- methoxy- pyrimidin- 2-amine

334.0 0.015 71 5-chloro-N-(1- (cyclopropyl- sulfonyl)- 3-methyl-1H-pyrazol-4-yl)-4- methoxy- pyrimidin- 2-amine

1H NMR (400 MHz, DMSO) δ 9.44 (s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H),4.01 (s, 3 H), 3.10-2.95 (m, 1 H), 2.31 (s, 3 H), 1.17 (m, 4 H). 0.02072 2-(4-(5-chloro-4- methoxy- pyrimidin- 2-ylamino)-5- methyl-1H-pyrazol-1-yl)-2- methylpropane- nitrile

1H NMR (400 MHz, DMSO) δ 8.98 (s, 1 H), 7.69 (s, 1 H), 7.06 (s, 1 H),3.91 (s, 3 H), 2.40 (s, 3 H), 1.95 (s, 6 H). 0.016 73 2-(4-(5-chloro-4-methoxy- pyrimidin- 2-ylamino)-3- methyl-1H- pyrazol-1-yl)-2-methylpropane- nitrile

1H NMR (400 MHz, DMSO) δ 9.11 (s, 1 H), 8.14 (s, 1 H), 7.07 (s, 1 H),3.98 (s, 3 H), 2.18 (s, 3 H), 1.93 (s, 7 H). 0.014 74 5-chloro-4-ethoxy- N-(5-methyl-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4-yl)pyrimidin-2- amine

1H NMR (400 MHz, DMSO) δ 8.84 (s, 1 H), 8.17 (s, 1 H), 7.84 (s, 1 H),4.41 (q, J = 7.0, 2 H), 4.31-4.16 (m, 1 H), 4.06-3.84 (m, 2 H), 3.44(td, J = 11.5, 2.7, 2 H), 2.11 (s, 3 H), 1.98- 1.77 (m, 4 H), 1.34 (t, J= 7.1, 3 H). 338.1 75 (5-Chloro-4- methoxy- pyrimidin-2- yl)-[1-(4-methanesulfonyl- phenyl)-3-methyl- 1H-pyrazol-4-yl]- amine

0.0022 76 (5-Chloro-4- methoxy- pyrimidin-2-yl)- (3-methyl-1- phenyl-1H-pyrazol-4-yl)- amine

0.0023 77 (4-Methoxy-5- trifluoromethyl- pyrimidin-2-yl)- (3-methyl-1-phenyl-1H- pyrazol-4-yl)- amine

0.0016 78 (4-Methoxy-5- trifluoromethyl- pyrimidin-2-yl)- (5-methyl-1-phenyl-1H- pyrazol-4-yl)- amine

0.0381 79 (5-Chloro-4- methoxy- pyrimidin-2-yl)- (1- methanesulfonyl-3-methyl-1H- pyrazol-4-yl)- amine

0.0078 80 (5-Chloro-4- methoxy- pyrimidin-2-yl)- [5-methyl-1-(tetrahydro- pyran-4-yl)-1H- pyrazol-4-yl]- amine

0.0663 81 4-[4-(5-Chloro- 4-methoxy- pyrimidin-2- ylamino)-3-methyl-pyrazol- 1-yl]-N,N- dimethyl- benzamide

0.0022 82 4-[4-(5-Chloro-4- methoxy- pyrimidin-2- ylamino)-5-methyl-pyrazol- 1-yl]-N,N- dimethyl- benzamide

0.63 83 4-[4-(5-Chloro- 4-methoxy- pyrimidin-2- ylamino)-5-methyl-pyrazol- 1-yl]- benzonitrile

0.0090 84 N²-(5-Methoxy- 1-methyl- 1H-pyrazol-4- yl)-N⁴-methyl- 5-trifluoromethyl- pyrimidine-2,4- diamine

0.0742 85 (5-Chloro-4- methoxy- pyrimidin-2-yl)- [5-chloro-1-(tetrahydro- pyran-4-yl)- 1H-pyrazol- 4-yl]-amine

0.0066 86 (5-Chloro-4- methoxy- pyrimidin-2-yl)- {1-[1-(2-fluoro-ethyl)-piperidin- 4-yl]-3- methyl-1H- pyrazol-4-yl}- amine

0.183 87 N²-[1-(1- [1,3]Dioxolan- 2-ylmethyl- piperidin-4-yl)-5-methyl-1H- pyrazol-4-yl]- N⁴-ethyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0008 88 N²-[1-(1- [1,3]Dioxolan-2- ylmethyl- piperidin-4-yl)-3-methyl-1H- pyrazol-4-yl]-N⁴- ethyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0094

Example 895-Bromo-N²-(1,5-dimethyl-1H-pyrazol-4-yl)-N⁴-methylpyrimidine-2,4-diamine

To a mixture of 5-bromo-2-chloro-N-methylpyrimidin-4-amine (0.201 g,0.903 mmol) and 1,5-dimethyl-1H-pyrazol-4-amine (0.12 g, 1.08 mmol) in2-methoxyethanol (2 mL) was added TFA (0.070 mL, 0.9 mmol). The reactionwas stirred in a sealed tube at 100° C. for 90 minutes. The resultingprecipitate was collected by filtration. The isolated solid was furtherpurified by reverse phase HPLC to give5-bromo-N²-(1,5-dimethyl-1H-pyrazol-4-yl)-N⁴-methylpyrimidine-2,4-diamine(46 mg, 17%). LCMS (Method A): [MH⁺]=297.0 at 2.57 min. ¹H-NMR (DMSO): δ8.28 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 6.79 (d, J=3.4, 1H), 3.67 (s,3H), 2.82 (d, J=3.6, 3H), 2.14 (s, 3H). Ki=0.017 uM.

Compounds made using the above procedure are shown in Table 8 below,together with low resolution mass spectrometry (M+H), proton NMR, andLRRK2 K_(i) (micromolar) data for selected compounds determined from theassay described below.

TABLE 8 Name Structure ¹H NMR M + H⁺ K_(I)  90 N²-(1,3-Dimethyl-1H-pyrazol-4-yl)- 5-iodo-N⁴-methyl- pyrimidine-2,4- diamine

¹H-NMR (DMSO): δ 8.24 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 6.46 (d, J= 4.3, 1 H), 3.70 (s, 3 H), 2.85 (d, J = 4.6, 3 H), 2.08 (s, 3 H). 345.0 91 N4-methyl-N2-(5- methyl-1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4-diamine

438.2 0.0041  92 N4-methyl-N2-(3- methyl-1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4-diamine

438.2 0.046  93 5-bromo-N4- methyl-N2-(5- methyl-1-(1-(2,2,2-trifluoroethyl) piperidin-4-yl)-1H- pyrazol-4- yl)pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.22 (s, 1 H), 7.84 (s, 1 H), 7.56 (s, 1 H),6.76 (d, J = 4.6, 1 H), 4.12-4.00 (m, 1 H), 3.22 (q, J = 10.2, 2 H),3.00 (d, J = 11.9, 2 H), 2.82 (d, J = 4.5, 3 H), 2.56 (d, J = 11.9, 2H), 2.01 (qd, J = 12.3, 3.7, 2 H), 1.75 (d, J = 13.4, 2 H). 0.0014  945-bromo-N4- methyl-N2-(3- methyl-1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H- pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.28 (s, 1 H), 7.86 (d, J = 13.2, 2 H), 6.80(d, J = 4.6, 1 H), 4.05-3.93 (m, 1 H), 3.21 (dd, J = 20.6, 10.3, 5 H),2.98 (d, J = 12.0, 2 H), 2.86 (d, J = 4.6, 3 H), 2.00- 1.80 (m, 5 H).0.013  95 5-bromo-N4- methyl-N2-(3- methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.45 (s, 1 H), 7.98 (s, 1 H), 7.91 (s, 1 H),6.86 (d, J = 4.4, 1 H), 4.96 (q, J = 9.2, 2 H), 2.87 (d, J = 4.6, 3 H),2.15 (s, 3 H). 0.0012  96 5-bromo-N4- methyl-N2-(5- methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.35 (s, 1 H), 7.86 (s, 1 H), 7.68 (s, 1 H),6.80 (d, J = 4.5, 1 H), 4.99 (q, J = 9.2, 2 H), 2.81 (d, J = 4.5, 3 H),2.20 (s, 3 H). 0.0011  97 N4-ethyl-N2-(3- methyl-1-(oxetan-3-yl)-1H-pyrazol- 4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.06* (br s, 1 H), 8.69† (br s, 1 H), 8.33† (s,1 H), 8.13* (s, 1 H), 8.09* (br s, 1 H), 7.94† (br s, 1 H), 7.09* (br s,1 H), 6.95† (br s, 1 H), 5.47 (p, J = 7.0, 1 H), 4.92-4.85 (m, 4 H),3.68-3.30 (m, 2 H), 2.21 (s, 3 H), 1.17 (t, J = 7.0, 3 H). [* and †denote rotameric peaks.] 343 0.0016  98 5-chloro-N4-ethyl-N2-(3-methyl-1- (oxetan-3-yl)-1H- pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.44 (br s, 1 H), 8.01 (s, 1 H), 7.87 (s, 1 H),7.10 (s, 1 H), 5.46 (t, J = 7.0, 1 H), 4.89 (dt, J = 22.1, 6.7, 4 H),3.44 (p, J = 6.7, 2 H), 2.20 (s, 3 H), 1.18 (t, J = 7.1, 3 H). 3090.0031  99 5-bromo-N4- methyl-N2-(1- methyl-1H- pyrazol-5-yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.04 (s, 1 H), 8.29 (s, 1 H), 7.99 (s, 1 H),7.32 (d, J = 2.0, 1 H), 7.05 (q, J = 4.7, 1 H), 6.23 (d, J = 2.0, 1 H),3.68 (s, 3 H), 2.86 (d, J = 4.7, 3 H). Note: formic acid salt. 2830.0054 100 2-methyl-1-(5- methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propan-2-ol

1H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1 H), 7.76 (br s, 1 H), 6.69 (br s, 1H), 5.15 (s, 1 H), 4.49 (s, 1 H), 3.97 (s, 2 H), 2.98 (d, J = 4.6, 3 H),2.21 (s, 3 H), 1.18 (s, 6 H). 345 0.0085 101 5-chloro-N4- methyl-N2-(3-methyl-1- (methylsulfonyl)- 1H-pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.43 (s, 1 H), 7.95 (s, 1 H),7.22 (d, J = 4.3, 1 H), 3.38 (s, 3 H), 2.91 (d, J = 4.6, 3 H), 2.31 (s,3 H). 0.0088 102 N4-methyl-N2-(3- methyl-1- (methylsulfonyl)-1H-pyrazol-4-yl)- 5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.35 (s, 1 H), 8.47 (s, 1 H), 8.20 (s, 1 H),7.17 (s, 1 H), 3.41 (s, 3 H), 2.93 (d, J = 4.4, 3 H), 2.32 (s, 3 H).0.0029 103 N4-methyl-N2-(3- methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 12.20 (d, J = 43.0, 1 H), 8.81 (s, 1 H), 8.06(s, 1 H), 7.79 (d, J = 67.1, 1 H), 6.90 (s, 1 H), 2.86 (s, 3 H), 2.15(s, 3 H). 0.0090 104 5-bromo-N4-ethyl- N2-(3-methyl-1- (oxetan-3-yl)-1H-pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.46 (br s, 1 H), 8.00 (s, 1 H), 7.94 (s, 1 H),6.90 (s, 1 H), 5.47-5.45 (m, 1 H), 4.89 (dt, J = 22.8, 6.7, 4 H), 3.44(p, J = 6.7, 2 H), 2.20 (s, 3 H), 1.18 (t, J = 7.1, 3 H). 353 0.0014 105N2-(1- (difluoromethyl)-3- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.04 (s, 1 H), 8.09 (s, 1 H), 7.98 (s, 1 H),7.71 (t, J = 58.1, 1 H), 7.01 (s, 1 H), 2.84 (s, 3 H), 2.34 (s, 3 H).0.0055 106 N2-(1- (difluoromethyl)-5- methyl-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.20 (s, 1 H), 8.31 (s, 1 H), 8.15 (s, 1 H),7.66 (t, J = 59.5, 1 H), 7.15 (s, 1 H), 2.91 (d, J = 4.4, 3 H), 2.24 (s,3 H). 0.0019 107 5-bromo-N4-ethyl- N2-(1-ethyl-5- methyl-1H- pyrazol-4-yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.20 (s, 1 H), 7.85 (s, 1 H), 7.49 (s, 1 H),6.72 (t, J = 5.5, 1 H), 4.00 (q, J = 7.2, 2 H), 3.35 (p, J = 6.9, 2 H),2.15 (s, 3 H), 1.27 (t, J = 7.2, 3 H), 1.10 (t, J = 7.1, 3 H). 0.00043108 5-bromo-N2-(1-(4- fluorophenyl)-3- methyl-1H- pyrazol-4-yl)-N4-methylpyrimidine- 2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.47 (s, 1 H), 7.88 (m, 2 H), 7.60-7.49 (m, 2H), 7.34 (t, J = 8.4, 2 H), 6.84 (s, 1 H), 2.86 (d, J = 3.8, 3 H), 2.23(s, 3 H). 0.0003 109 5-bromo-N4- methyl-N2-(3- methyl-1-phenyl-1H-pyrazol-4- yl)pyrimidine-2,4- diamine

360 0.0084 110 5-bromo-N4- methyl-N2-(5- methyl-1-phenyl- 1H-pyrazol-4-yl)pyrimidine-2,4- diamine

360 111 5-bromo-N4- methyl-N2-(1- methyl-1H- pyrazol-4-yl)pyrimidine-2,4- diamine

112 N4-methyl-N2-(3- methyl-1-(1- (methylsulfonyl) azetidin-3-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (300MHz, CD₃OD) δ 8.12 (s, 1 H), 7.93 (s, 1 H), 5.22-5.13 (m, 1H), 4.35-4.30 (m, 4 H), , 3.31 (s, 3 H), 3.31 (s, 3 H), 2.24 (s, 3 H)113 5-bromo-N4- methyl-N2-(3- methyl-1-propyl- 1H-pyrazol-4-yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.22 (s, 1 H), 7.84 (s, 1 H), 7.51 (s, 1 H),6.75 (d, J = 4.0, 1 H), 3.92 (t, J = 7.0, 2 H), 2.81 (d, J = 4.3, 3 H),2.15 (s, 3 H), 1.70 (h, J = 7.2, 2 H), 0.83 (t, J = 7.4, 3 H). 0.012 1145-chloro-N4- methyl-N2-(3- methyl-1-((3- methyloxetan-3- yl)methyl)-1H-pyrazol-4- yl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.36 (s, 1 H), 7.84 (s, 1 H), 7.82 (s, 1 H),7.04 (q, J = 4.7, 1 H), 4.57 (d, J = 5.8, 2 H), 4.20 (d, J = 6.0, 3 H),3.44 (br s, 2 H), 2.86 (d, J = 4.6, 3 H), 2.11 (s, 2 H), 1.14 (s, 3 H).323 0.019 115 5-bromo-N2-(1- (3,5- difluorophenyl)-5- methyl-1H-pyrazol-4-yl)-N4- methylpyrimidine- 2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.67 (s, 1 H), 8.61 (s, 1 H), 7.96 (s, 1 H),7.45 (d, J = 8.2, 2 H), 7.06 (t, J = 9.2, 1 H), 6.93 (d, J = 4.3, 1 H),2.91 (d, J = 4.5, 3 H), 2.25 (s, 3 H). 0.031 116 5-bromo-N2-(1- (3,5-difluorophenyl)-3- methyl-1H- pyrazol-4-yl)-N4- methylpyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.55 (s, 1 H), 7.96 (s, 1 H), 7.90 (s, 1 H),7.40-7.20 (m, 3 H), 6.86 (d, J = 4.4, 1 H), 2.86 (d, J = 4.5, 3 H), 2.34(s, 3 H). 0.0003 117 N4-methyl-N2-(3- methyl-1-(pyridin-2-yl)-1H-pyrazol- 4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.20 (s, 2 H), 8.40 (d, J = 4.7, 1 H), 8.18 (s,1 H), 7.91 (t, J = 7.8, 1 H), 7.83 (d, J = 8.2, 1 H), 7.29-7.19 (m, 1H), 7.08 (s, 1 H), 2.96 (d, J = 3.9, 3 H), 2.32 (s, 3 H). 0.0067 118N4-methyl-N2-(3- methyl-1-((3- methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1 H), 7.83 (s, 1 H), 6.59 (br s, 1H), 5.18 (br s, 1 H), 4.69 (d, J = 6.1, 2 H), 4.39 (d, J = 6.1, 2 H),4.24 (s, 2 H), 3.05 (d, J = 4.7, 3 H), 2.24 (s, 3 H), 1.28 (s, 3 H). 3570.0072 119 N4-methyl-N2-(5- methyl-1-propyl- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.86 (s, 1 H), 8.07 (s, 1 H), 7.85 (s, 1 H),6.93 (s, 1 H), 3.92 (t, J = 6.8, 2 H), 2.87 (d, J = 4.0, 3 H), 2.11 (s,3 H), 1.73 (h, J = 7.1, 2 H), 0.82 (t, J = 7.3, 3 H). 0.0056 120N4-methyl-N2-(3- methyl-1-propyl- 1H-pyrazol-4-yl)- 5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.80 (s, 1 H), 8.04 (s, 1 H), 7.61 (s, 1 H),6.88 (s, 1 H), 3.94 (t, J = 7.0, 2 H), 2.82 (s, 3 H), 2.12 (d, J = 39.3,3 H), 1.71 (h, J = 7.3, 2 H), 0.84 (t, J = 7.3, 3 H). 0.0006 1215-bromo-N2-(1- isopropyl-3- methyl-1H- pyrazol-4-yl)-N4-methylpyrimidine- 2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.28 (s, 1 H), 7.88 (s, 1 H), 7.83 (s, 1 H),6.80 (d, J = 4.3, 1 H), 4.39-4.26 (m, 1 H), 2.86 (d, J = 4.6, 3 H), 2.10(s, 3 H), 1.36 (d, J = 6.7, 6 H). 0.0031 122 5-bromo-N2-(1-(4-chlorophenyl)-5- methyl-1H- pyrazol-4-yl)-N4- methylpyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.64 (s, 1 H), 8.55 (s, 1 H), 7.95 (s, 1 H),7.72 (d, J = 8.9, 2 H), 7.49 (d, J = 8.9, 2 H), 6.92 (d, J = 4.4, 1 H),2.91 (d, J = 4.5, 3 H), 2.25 (s, 3 H). 0.014 123 N2-(1-(4-chlorophenyl)-5- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.03 (s, 1 H), 8.05 (d, J = 33.8, 2 H), 7.57(s, 4 H), 6.76 (d, J = 171.5, 2 H), 2.88 (d, J = 3.9, 3 H), 2.28 (s, 3H). 0.0003 124 N4-methyl-N2-(3- methyl-1-(4- (methylsulfonyl)phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 8.07 (t, J = 13.9, 3 H), 7.84(d, J = 11.0, 2 H), 7.00 (s, 1 H), 3.28 (s, 3 H), 2.88 (d, J = 4.0, 3H), 2.37 (s, 3 H). 0.0003 125 N4-methyl-N2-(5- methyl-1-(4-(methylsulfonyl) phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.24 (s, 1 H), 8.75 (s, 1 H), 8.16 (s, 1 H),8.02-7.91 (m, 4 H), 7.09 (s, 1 H), 3.23 (s, 3 H), 2.95 (d, J = 4.3, 3H), 2.31 (s, 3 H). 0.0047 126 N2-(1-((1S,5S)-8- oxabicyclo[3.2.1]octan-3-yl)-3- methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H NMR (300 MHz, CD₃OD) δ 8.05 (s, 2 H), 4.37-4.46 (m, 3 H), 3.00 (s, 3H), 2.45-2.42 (m, 4 H), 2.25 (s, 3 H), 1.79- 1.77 (m, 4 H) 0.113 127N2-(1-butyl-5- methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

329.2 0.0003 128 N4-methyl-N2-(3- methyl-1- (pyrimidin-2-yl)-1H-pyrazol-4-yl)- 5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.28 (s, 1 H), 8.96 (s, 1 H), 8.78 (d, J = 4.8,2 H), 8.19 (s, 1 H), 7.35 (t, J = 4.8, 1 H), 7.11 (s, 1 H), 2.97 (d, J =4.0, 3 H), 2.33 (s, 3 H). 0.0114 129 N2-(1-(4- chlorophenyl)-3-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 9.16 (s, 1 H), 8.60 (s, 1 H), 8.14 (s, 1 H),7.74 (d, J = 8.8, 2 H), 7.50 (d, J = 8.9, 2 H), 7.05 (s, 1 H), 2.93 (d,J = 4.4, 3 H), 2.26 (s, 3 H). 0.028 130 N2-(1-(2- fluoroethyl)-3-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.97 (s, 1 H), 8.08 (s, 1 H), 7.93 (s, 1 H),7.25-6.91 (m, 1 H), 4.77 (t, J = 4.7, 1 H), 4.65 (t, J = 4.7, 1 H), 4.33(t, J = 4.7, 1 H), 4.26 (t, J = 4.7, 1 H), 2.88 (d, J = 4.3, 3 H), 2.13(s, 3 H). 0.0011 131 N4-methyl-N2-(3- methyl-1-(1- (oxetan-3-yl)piperidin-4-yl)- 1H-pyrazol-4-yl)- 5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.90 (s, 1 H), 8.07 (s, 1 H), 7.93 (s, 1 H),6.95 (s, 1 H), 4.54 (t, J = 6.5, 2 H), 4.43 (t, J = 6.1, 2 H), 4.00 (s,1 H), 3.49-3.38 (m, 1 H), 2.88 (d, J = 4.4, 3 H), 2.76 (d, J = 9.5, 2H), 2.12 (s, 3 H), 2.04-1.72 (m, 6 H). 0.0374 132 N4-methyl-N2-(5-methyl-1-(1- (oxetan-3- yl)piperidin-4-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.84 (s, 1 H), 8.04 (s, 1 H), 7.71 (s, 1 H),6.89 (s, 1 H), 4.55 (t, J = 6.3, 2 H), 4.45 (t, J = 5.5, 2 H), 4.07 (s,1 H), 3.54-3.37 (m, 1 H), 2.84 (t, J = 19.1, 5 H), 2.19 (s, 3 H), 1.99(td, J = 23.4, 11.5, 4 H), 1.80 (d, J = 11.5, 2 H). 133 N2-(1-(2-fluoroethyl)-5- methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.05 (s, 1 H), 7.69 (s, 1 H),6.91 (s, 1 H), 4.77 (t, J = 4.8, 1 H), 4.66 (t, J = 4.8, 1 H), 4.35 (t,J = 4.8, 1 H), 4.28 (t, J = 4.8, 1 H), 2.84 (s, 3 H), 2.18 (s, 3 H).0.0018 134 1-(4-(4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-3- methyl-1H- pyrazol-1- yl)piperidin-1- yl)ethanone

1H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.05 (s, 1 H), 7.61 (s, 1 H),6.87 (s, 1 H), 4.47 (d, J = 13.6, 1 H), 4.42- 4.25 (m, 1 H), 3.92 (d, J= 13.6, 1 H), 3.38 (m, 2 H), 3.20 (t, J = 11.5, 1 H), 2.70 (m, 1 H),2.27 (d, J = 46.8, 3 H), 1.83 (m, 4 H), 1.08 (m, 3 H). 0.0022 135cyclopropyl(4-(5- methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)piperidin-1- yl)methanone

1H NMR (400 MHz, DMSO) δ 8.85 (s, 1 H), 8.05 (s, 1 H), 7.71 (s, 1 H),6.89 (s, 1 H), 4.55-4.23 (m, 3 H), 2.84 (s, 4 H), 2.22 (s, 3 H), 1.91(m, 5 H), 0.79-0.62 (m, 4 H). 0.0010 136 cyclopropyl(4-(3- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)piperidin-1- yl)methanone

1H NMR (400 MHz, DMSO) δ 8.90 (s, 1 H), 8.10 (s, 1 H), 7.95 (s, 1 H),6.95 (s, 1 H), 4.35 (m, 3 H), 3.24 (m, 1 H), 2.88 (d, J = 4.3, 3 H),2.74 (m, 1 H), 2.04 (m, 6 H), 1.75 (m, 2 H), 0.72 (m, 4 H). 0.0093 1371-(4-(4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-5-methyl-1H- pyrazol-1- yl)piperidin-1- yl)ethanone

1H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.05 (s, 1 H), 7.61 (s, 1 H),6.87 (s, 1 H), 4.47 (d, J = 13.6, 1 H), 4.42- 4.25 (m, 1 H), 3.92 (d, J= 13.6, 1 H), 3.38 (m, 2 H), 3.20 (t, J = 11.5, 1 H), 2.70 (m, 1 H),2.27 (d, J = 46.8, 3 H), 1.83 (m, 4 H), 1.08 (m, 3 H). 0.0004 138N2-(5-chloro-1- isopropyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.98 (br s, 1 H), 8.12 (s, 1 H), 7.85 (s, 1 H),7.05 (s, 1 H), 4.65 (p, J = 6.6, 1 H), 2.86 (s, 3 H), 1.42 (d, J = 6.6,6 H). 335 0.0011 139 N2-(5-chloro-1- ethyl-1H-pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1 H), 8.08 (s, 1 H), 6.68 (br s, 1H), 5.21 (s, 1 H), 4.18 (q, J = 7.3, 2 H), 3.07 (d, J = 4.7, 3 H), 1.44(t, J = 7.3, 3 H). 321 0.0020 140 N4-methyl-N2-(3- methyl-1-(pyrimidin-5-yl)- 1H-pyrazol-4-yl)- 5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 9.19 (m, 3 H), 9.06 (s, 1 H), 8.76 (s, 1 H),8.16 (s, 1 H), 7.10 (s, 1 H), 2.96 (d, J = 4.3, 3 H), 2.31 (s, 3 H).0.0061 141 N4-methyl-N2-(4- methyl-1-(1- methylpiperidin-4-yl)-1H-pyrazol-3- yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

370.2 0.041 142 N4-methyl-N2-(5- methyl-1-(2- methylpyridin-4-yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.11 (s, 1 H), 8.52 (d, J = 5.5, 1 H), 8.10 (s,2 H), 7.50 (s, 1 H), 7.43 (dd, J = 5.5, 1.9, 1 H), 6.99 (s, 1 H), 2.87(d, J = 3.5, 3 H), 2.54 (s, 3 H), 2.40 (s, 3 H). 0.0003 143N4-methyl-N2-(3- methyl-1-(2- methylpyridin-4- yl)-1H-pyrazol-4- yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.19 (s, 1 H), 8.72 (s, 1 H), 8.42 (d, J = 5.6,1 H), 8.16 (s, 1 H), 7.59 (s, 1 H), 7.49 (d, J = 4.7, 1 H), 7.09 (s, 1H), 2.95 (d, J = 4.3, 3 H), 2.29 (s, 3 H). 0.0069 144 N4-ethyl-N2-(3-methyl-1-((3- methyloxetan-3- yl)methyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1 H), 7.79 (s, 1 H), 6.58 (br s, 1H), 5.10 (br s, 1 H), 4.69 (d, J = 6.0, 2 H), 4.39 (d, J = 6.0, 2 H),4.24 (s, 2 H), 3.52 (p, J = 6.6, 2 H), 2.23 (s, 3 H), 1.28 (s, 3 H),1.28 (t, J = 6.6, 3 H). 371 0.0009 145 N2-(5-chloro-1- cyclopropyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1 H), 8.04 (s, 1 H), 6.76 (br s, 1H), 5.21 (s, 1 H), 3.48-3.42 (m, 1 H), 3.06 (d, J = 4.7, 3 H), 1.23-1.19(m, 2 H), 1.10-1.04 (m, 2 H). 333 0.0017 146 N2-(5-chloro-1-(cyclopropyl- methyl)-1H- pyrazol-4- yl)-N4-methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1 H), 8.10 (s, 1 H), 6.72 (br s, 1H), 5.21 (s, 1 H), 4.00 (d, J = 7.0, 2 H), 3.07 (d, J = 4.7, 3 H),1.34-1.25 (m, 1 H), 0.62-0.56 (m, 2 H), 0.44- 0.39 (m, 2 H). 347 0.0003147 4-(5-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)benzonitrile

1H NMR (400 MHz, DMSO) δ 9.20 (s, 1 H), 8.73 (s, 1 H), 8.16 (s, 1 H),7.91 (s, 4 H), 7.09 (s, 1 H), 2.94 (d, J = 4.3, 3 H), 2.29 (s, 3 H).0.017 148 4-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)benzonitrile

1H NMR (400 MHz, DMSO) δ 9.07 (s, 1 H), 8.10 (s, 1 H), 7.98 (d, J = 8.6,2 H), 7.78 (d, J = 8.6, 1 H), 6.99 (s, 1 H), 2.88 (d, J = 3.8, 2 H),2.36 (s, 2 H). 0.0003 149 N4-methyl-N2-(3- methyl-1- (tetrahydrofuran-3-yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.95 (s, 1 H), 8.08 (s, 1 H), 7.99 (s, 1 H),6.96 (s, 1 H), 4.88 (m, 1 H), 3.99-3.74 (m, 4 H), 2.89 (d, J = 4.4, 3H), 2.33 (m, 1 H), 2.13 (m, 4 H). 0.0068 150 N4-methyl-N2-(5- methyl-1-(tetrahydrofuran-3- yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.05 (s, 1 H), 7.61 (d, J =92.3, 1 H), 6.90 (s, 1 H), 5.10-4.58 (m, 1 H), 4.19-3.69 (m, 4 H), 2.84(m, 3 H), 2.42-2.04 (m, 5 H). 0.0051 151 5-(4-(4- (ethylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-5- methyl-1H- pyrazol-1-yl)-1-methylpiperidin-2- one

1H NMR (400 MHz, DMSO) δ 8.84 (s, 1 H), 8.05 (s, 1 H), 7.66 (s, 1 H),6.89 (s, 1 H), 4.81-4.63 (m, 1 H), 3.61 (m, 1 H), 3.50 (m, 1 H), 3.38(m, 2 H), 2.82 (m, 3 H), 2.49- 2.09 (m, 6 H), 1.99 (m, 1 H), 1.08 (m, 3H). 0.0011 152 5-(4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-3- methyl-1H- pyrazol-1-yl)-1- methylpiperidin-2- one

1H NMR (400 MHz, DMSO) δ 8.90 (s, 1 H), 8.08 (s, 1 H), 7.90 (s, 1 H),6.95 (s, 1 H), 4.58 (m, 1 H), 3.68-3.53 (m, 2 H), 3.42 (m, 2 H), 2.82(m, 3 H), 2.45-2.18 (m, 3 H), 2.13 (m, 4 H), 1.12 (m, 3 H). 0.0073 1535-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)piperidin-2- one

1H NMR (400 MHz, DMSO) δ 8.95 (s, 1 H), 8.05 (d, J = 23.6, 2 H), 7.50(s, 1 H), 6.97 (s, 1 H), 4.49 (m, 1 H), 3.47 (m, 2 H), 2.88 (d, J = 4.3,3 H), 2.39- 1.97 (m, 7 H). 0.0097 154 5-(5-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)piperidin-2-one

1H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.05 (s, 1 H), 7.62 (d, J =96.3, 2 H), 6.90 (s, 1 H), 4.59 (m, 1 H), 3.55- 3.42 (m, 1 H), 3.36 (m,1 H), 2.84 (m, 3 H), 2.30 (m, 6 H), 1.99 (m, 1 H). 0.0022 155N2-(1-isopropyl-5- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (500 MHz, DMSO) δ 8.08 (s, 1 H), 7.88 (s, 1 H), 6.80 (s, 1 H),5.15 (s, 1 H), 4.39-4.44 (m, 1 H), 3.01 (d, J = 5, 3 H), 2.22 (s, 3 H),1.49 (d, J = 6.5, 6 H). 315 0.0025 156 N,N-dimethyl-4- (5-methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)benzamide

1H NMR (400 MHz, DMSO) δ 9.07 (s, 1 H), 8.10 (s, 1 H), 7.57 (q, J = 8.5,4 H), 6.98 (s, 1 H), 2.99 (s, 6 H), 2.88 (d, J = 4.0, 3 H), 2.31 (s, 3H). 0.0003 157 4-(4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-5- methyl-1H- pyrazol-1-yl)-N,N- dimethylbenzamide

1H NMR (400 MHz, DMSO) δ 9.00 (s, 1 H), 8.24-7.78 (m, 2 H), 7.57 (q, J =8.5, 4 H), 6.95 (s, 1 H), 3.43 (s, 2 H), 2.99 (s, 6 H), 2.31 (s, 3 H),1.12 (t, J = 6.7, 3 H). 0.0003 58 N4-ethyl-N2-(5- methyl-1-(tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.80 (s, 1 H), 8.05 (s, 1 H), 7.63 (s, 1 H),6.87 (s, 1 H), 4.41-4.24 (m, 1 H), 3.95 (dd, J = 11.2, 4.0, 2 H), 3.47(t, J = 11.2, 2 H), 3.38 (s, 2 H), 2.20 (s, 3 H), 2.01 (qd, J = 12.4,4.5, 2 H), 1.85-1.64 (m, 2 H), 1.08 (s, 3 H). 0.0003 159 N4-ethyl-N2-(3-methyl-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.08 (s, 1 H), 7.87 (s, 1 H),6.98 (s, 1 H), 4.42-4.15 (m, 1 H), 3.94 (d, J = 11.0, 2 H), 3.44 (t, J =11.0, 3 H), 2.12 (s, 2 H), 1.89 (s, 3 H), 1.21-1.00 (m, 2 H). 0.0039 160N4-ethyl-N2-(3- methyl-1- (methylsulfonyl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.38 (s, 1 H), 8.44 (s, 1 H), 8.20 (s, 1 H),7.24 (s, 1 H), 3.47 (p, J = 6.8, 2 H), 3.40 (s, 3 H), 2.32 (s, 3 H),1.21-1.09 (m, 3 H). 0.0003 161 N2-(1-(4- (cyclopropyl- sulfonyl)phenyl)-3-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 8.11 (s, 1 H), 8.02 (d, J = 8.6,3 H), 7.84 (d, J = 8.6, 2 H), 7.00 (s, 1 H), 3.01-2.82 (m, 4 H), 2.37(s, 3 H), 1.22-1.14 (m, 2 H), 1.14-0.94 (m, 2 H). 0.0003 162 4-(4-(4-(ethylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-5- methyl-1H-pyrazol-1- yl)benzonitrile

1H NMR (400 MHz, DMSO) δ 9.06 (s, 1 H), 8.10 (s, 1 H), 7.99 (d, J = 8.6,2 H), 7.78 (d, J = 8.6, 2 H), 6.97 (s, 1 H), 3.43 (s, 2 H), 2.36 (s, 3H), 1.12 (t, J = 6.8, 3 H). 0.0003 163 N4-ethyl-N2-(5- methyl-1-(4-(methylsulfonyl) phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.09 (s, 1 H), 8.15-8.02 (m, 3 H), 7.84 (d, J =8.7, 2 H), 6.97 (s, 1 H), 3.43 (s, 2 H), 2.37 (s, 3 H), 1.12 (t, J =7.0, 3 H). 0.0003 164 N,N-dimethyl-4- (3-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)benzamide

1H NMR (400 MHz, DMSO) δ 9.17 (s, 1 H), 8.65 (s, 1 H), 8.14 (s, 1 H),7.76 (d, J = 8.5, 2 H), 7.50 (d, J = 8.6, 2 H), 7.06 (s, 1 H), 3.06-2.86(m, 9 H), 2.28 (s, 3 H). 0.0057 165 N2-(1- (cyclopropyl-methyl)-5-methyl- 1H-pyrazol-4-yl)- N4-methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.41 (d, J = 16.0, 1 H), 8.04 (s, 1 H), 6.59(s, 1 H), 6.59 (s, 1 H), 3.89 (m, J = 11.0, 2 H), 3.85 (d, J = 7.5, 3H), 2.17 (s, 1 H), 1.13-1.18 (m, 1 H), 0.44- 0.50 (m, 2 H), 0.28-0.32(s, 2 H). 327 0.0012 166 N2-(1- (cyclopropyl- methyl)-3-methyl-1H-pyrazol-4-yl)- N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.46 (d, J = 2.0, 1 H), 8.14 (s, 1 H), 8.04 (s,1 H), 6.65 (s, 1 H), 3.82-3.84 (m, 2 H), 2.90 (d, J = 7.5, 3 H), 1.89(s, 1 H), 1.15-1.20 (m, 1 H), 0.47-0.53 (m, 2 H), 0.28-0.33 (s, 2 H).0.0045 167 N2-(1-(4- (cyclopropyl- sulfonyl)phenyl)- 5-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.24 (s, 1 H), 8.75 (s, 1 H), 8.16 (s, 1 H),8.02-7.87 (m, 4 H), 7.09 (s, 1 H), 2.96 (d, J = 4.3, 3 H), 2.92-2.81 (m,1 H), 2.31 (s, 3 H), 1.21- 1.11 (m, 2 H), 1.10-0.97 (m, 2 H). 0.0188 168N2-(5-chloro-1- (oxetan-3-yl)-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1 H), 8.13 (s, 1 H), 6.89 (br s, 1H), 5.56 (p, J = 7.1, 1 H), 5.25 (s, 1 H), 5.19 (t, J = 6.6, 2 H), 5.00(t, J = 7.2, 2 H), 3.08 (d, J = 4.7, 3 H). 349 0.0095 169N4-ethyl-N2-(5- methyl-1-((3- methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1 H), 7.70 (br s, 1 H), 6.41 (br s, 1H), 5.04 (s, 1 H), 4.78 (d, J = 6.1, 2 H), 4.40 (d, J = 6.1, 2 H), 4.22(s, 2 H), 3.46 (p, J = 6.6, 2 H), 2.20 (s, 3 H), 1.25 (s, 3 H), 1.21 (t,J = 7.0, 3 H). 371 0.0022 170 N2-(1- (cyclopropyl- sulfonyl)-3-methyl-1H-pyrazol-4-yl)- N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.36 (s, 1 H), 8.44 (s, 1 H), 8.19 (s, 1 H),7.18 (s, 1 H), 3.07-2.96 (m, 1 H), 2.92 (d, J = 4.4, 3 H), 2.32 (s, 3H), 1.24-1.07 (m, 4 H). 0.002 171 N2-(1- (cyclopropyl-sulfonyl)-3-methyl- 1H-pyrazol-4-yl)- N4-ethyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.36 (s, 1 H), 8.41 (s, 1 H), 8.19 (s, 1 H),7.23 (s, 1 H), 3.47 (m, 2 H), 2.99 (m, 1 H), 2.32 (s, 3 H), 1.23-1.04(m, 7 H). 0.0009 172 5-chloro-N4-(2,2- difluoroethyl)-N2-(1,5-dimethyl-1H- pyrazol-4- yl)pyrimidine-2,4- diamine

0.0070 173 5-chloro-4-methyl- N-(3-methyl-1-(4- (methylsulfonyl)phenyl)-1H-pyrazol- 4-yl)pyrimidin-2- amine

1H NMR (400 MHz, DMSO) δ 9.10 (s, 1 H), 8.31 (s, 1 H), 8.06 (d, J = 8.6,2 H), 7.93 (s, 1 H), 7.85 (d, J = 8.6, 2 H), 3.28 (s, 6 H), 2.40 (s, 3H), 2.34 (s, 3 H). 0.484 174 N2-(1-(4- (cyclopropyl- sulfonyl)phenyl)-5-methyl-1H- pyrazol-4-yl)-N4- ethyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.21 (s, 1 H), 8.68 (s, 1 H), 8.17 (s, 1 H),7.95 (q, J = 9.0, 4 H), 7.09 (s, 1 H), 3.58-3.43 (m, 2 H), 2.95-2.79 (m,1 H), 2.31 (s, 3 H), 1.12 (ddd, J = 34.8, 14.3, 8.6, 7 H). 0.0011 1752-methyl-1-(4-(5- methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)piperidin-1- yl)propan-1-one

426 0.0068 176 N4-ethyl-N2-(1- methyl-1H- pyrazol-5-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

0.011 177 N2-(3-cyclopropyl- 1-methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

0.0067 178 N2-(5-cyclopropyl- 1-methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

0.012 179 N4-methyl-N2-(5- methyl-1-((3- methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1 H), 7.73 (br s, 1 H), 6.50 (br s, 1H), 5.13 (s, 1 H), 4.78 (d, J = 6.1, 2 H), 4.40 (d, J = 6.1, 2 H), 4.22(s, 2 H), 2.99 (d, J = 4.7, 3 H), 2.20 (s, 3 H), 1.25 (s, 3 H). 3570.0090 180 N2-(5-chloro-1- ((3-methyloxetan- 3-yl)methyl)-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1 H), 8.11 (s, 1 H), 6.68 (br s, 1H), 5.22 (s, 1 H), 4.78 (d, J = 6.2, 2 H), 4.40 (d, J = 6.2, 2 H), 4.33(s, 2 H), 3.06 (d, J = 4.7, 3 H), 1.28 (s, 3 H). 377 0.0056 181l-(4-(4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-5-methyl-1H- pyrazol-1- yl)piperidin-1-yl)- 2-methylpropan-1- one

1H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.05 (s, 1 H), 7.62 (s, 1 H),6.88 (s, 1 H), 4.51 (d, J = 11.9, 1 H), 4.45- 4.30 (m, 1 H), 4.06 (d, J= 12.8, 1 H), 3.37 (s, 2 H), 3.20 (m, 1 H), 2.92 (m, 1 H), 2.80-2.60 (m,1 H), 2.21 (s, 3 H), 1.88 (m, 4 H), 1.02 (m, 8 H). 0.00082 182N4-ethyl-N2-(3- methyl-1-(1- (oxetan-3- yl)azetidin-3-yl)-1H-pyrazol-4-yl)- 5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.83 (s, 1 H), 8.05 (s, 1 H), 7.73 (s, 1 H),6.87 (s, 1 H), 4.98 (p, J = 7.2, 1 H), 4.60 (t, J = 6.6, 2 H), 4.43 (t,J = 5.8, 2 H), 3.88-3.77 (m, 1 H), 3.70 (t, J = 7.3, 2 H), 3.56 (t, J =7.3, 2 H), 3.39 (s, 2 H), 2.16 (s, 3 H), 1.09 (s, 3 H). 0.0015 183cyclopropyl(4-(4- (4-(ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-3- methyl-1H- pyrazol-1- yl)piperidin-1- yl)methanone

438.3 0.0006 184 cyclopropyl(4-(4- (4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-5- methyl-1H- pyrazol-1- yl)piperidin-1-yl)methanone

438.3 0.0047 185 1-(5-chloro-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropan-2-ol

1H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1 H), 8.13 (s, 1 H), 6.81 (br s, 1H), 5.23 (s, 1 H), 4.09 (s, 2 H), 3.99 (s, 1 H), 3.06 (d, J = 4.7, 3 H),1.19 (s, 6 H). 365 0.0069 186 N4-ethyl-N2-(1- ethyl-1H-pyrazol- 3-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.66 (s, 1 H), 8.10 (s, 1 H), 7.58 (d, J = 2.0,1 H), 7.02 (s, 0 H), 7.00 (s, 1 H), 6.54 (d, J = 2.0, 1 H), 4.02 (q, J =7.2, 2 H), 3.57-3.37 (m, 2 H), 1.35 (t, J = 7.2, 3 H), 1.15 (t, J = 7.1,3 H). 0.0019 187 (S)-N2-(1-(2- methoxypropyl)-5- methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

345 0.0188 188 N2-(1-(2- methoxycyclo- pentyl)-3-methyl-1H-pyrazol-4-yl)- N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.49 (s, 1 H), 8.07 (s, 1 H), 6.68 (d, J = 2.5,1 H), 4.41 (m, 1 H), 3.95 (m, 1 H), 3.18 (s, 1 H), 2.91 (d, J = 8.0, 3H), 2.09 (s, 3 H), 1.64-192 (m, 6 H). 0.012 189 (S)-N2-(1-(2-methoxypropyl)-3- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.11 (s, 1 H), 7.90 (s, 1 H), 6.71 (s, 1 H),5.20 (s, 1 H), 3.00-4.07 (m, 2 H), 3.68-3.74 (m, 1 H), 3.32 (s, 3 H),3.00-3.06 (t, J = 3 Hz, 3 H), 2.25 (d, J = 3 Hz, 3 H), 1.14-1.18 (m, 3H). 0.0118 190 N2-(1-(1-methoxy- 2-methylpropan-2- yl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, MeOD) δ 8.01 (s, 1 H), 7.79 (s, 1 H), 3.58 (s, 2 H),3.27 (s, 3 H), 2.99 (s, 3 H), 2.22 (s, 3 H), 1.55 (s, 6 H). 0.0069 191N2-(1-(2,6- dimethyltetrahydro- 2H-pyran-4-yl)-3- methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, CDCl3) δ 8.54 (s, 1 H), 8.08 (s, 1 H), 7.98 (s, 1 H),6.70 (s, 1 H), 4.47 (s, 1 H), 3.70-3.80 (m, 2 H), 2.90 (d, J = 7.5, 3H), 2.13-2.24 (m, 5 H), 1.56-1.66 (m, 2 H), 1.16 (d, J = 6.5, 6 H).0.0846 192 (R)-N2-(1-(2- methoxypropyl)-5- methyl-1H-pyrazol-4-yl)-N4-methyl- 5-(trifluoromethyl) pyrimidine-2,4- diamine

345 0.0063 193 N2-(1-(3- methoxycyclo- pentyl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H-NMR (500 MHz, DMSO) δ 8.46 (br s, 1 H), 8.04 (s, 1 H), 7.85 (s, 1 H),6.85 (br s, 1 H), 4.48-4.54 (m, 1 H), 3.80-3.84 (m, 1 H), 3.20 (s, 3 H),2.89 (d, J = 7.0, 3 H), 2.35-2.45 (m, 1 H), 2.10 (s, 3 H), 1.84-2.08 (m,3 H), 1.74-1.81 (m, 2 H). 0.019 194 N4-methyl-N2-(1- methyl-5-(methylamino)-1H- pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.75-8.24 (m, 1 H), 8.06 (s, 1 H), 7.56-7.06(m, 1 H), 7.01- 6.82 (m, 1 H), 4.89-4.66 (m, 1 H), 3.59 (s, 3 H), 2.87(br s, 3 H), 2.68 (d, J = 5.1, 3 H). 302 0.0522 195 N4-methyl-N2-(5-methyl-1- (methylsulfonyl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.43 (s, 1 H), 8.47 (s, 1 H), 8.20 (s, 1 H),7.20 (s, 1 H), 3.41 (s, 3 H), 2.93 (d, J = 4.4, 3 H), 2.32 (s, 3 H).0.010 196 N4-methyl-N2-(5- methyl-1- (tetrahydro-2H- 1,1-dioxo-thiopyran-4-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (500 MHz, DMSO) δ 8.45 (d, J = 12, 1 H), 8.01 (d, J = 7.5, 1 H),7.59 (s, 1 H), 6.59-6.64 (m, 1 H), 4.49-4.56 (m, 1 H), 3.26-3.35 (t, J =20.5, 2 H), 3.16 (d, J = 20.5, 2 H), 2.82 (d, J = 6.0, 3 H), 2.34-2.45(m, 2 H), 2.11-2.17 (m, 5 H). 0.047 197 2-methyl-1-(4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-5-(trifluoromethyl)- 1H-pyrazol-1- yl)propan-2-ol

399.1 0.026 198 2-methyl-1-(4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-3- (trifluoromethyl)- 1H-pyrazol-1- yl)propan-2-ol

399.1 0.027 199 N2-(1-(3-fluoro-1- (oxetan-3- yl)piperidin-4-yl)-3-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

430.2 0.0022 200 (R)-N2-(1-(1- methoxypropan-2- yl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

345 0.0128 201 1-(3-tert-butyl-4- (4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropan-2-ol

401.2 0.42 202 N4-methyl-N2-(3- methyl-1-(1-(2,2,2- trifluoroethyl)azetidin-3-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 9.01 (s, 1 H), 8.13 (d, J = 36.8, 2 H), 7.01(s, 2 H), 4.93 (p, J = 6.9, 1 H), 3.82 (t, J = 7.6, 2 H), 3.58 (d, J =6.9, 2 H), 2.90 (d, J = 4.4, 3 H), 2.15 (s, 4 H). 0.034 203N2-(1-(1-methoxy- 2-methylpropan-2- yl)-5-methyl-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, MeOD) δ 7.97 (s, 1 H), 7.49 (s, 1 H), 3.67 (s, 2 H),3.31 (s, 3 H), 2.96 (s, 3 H), 2.36 (s, 3 H), 1.65 (s, 6 H). 0.042 204(R)-N4-methyl- N2-(3-methyl-1-(1- (oxetan-3- yl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 9.01 (s, 1 H), 8.12 (d, J = 19.5 Hz, 2 H), 7.04(s, 1 H), 4.75-4.80 (m, 1 H), 4.55-4.59 (m, 2 H), 4.42-4.47 (m, 2 H),3.61 (t, J = 6.0 Hz, 1 H), 2.92 (s, 3 H), 2.75 (s, 3 H), 2.32- 2.42 (m,2 H), 1.97-2.14 (m, 4 H). 0.029 205 (R)-N2-(1-(1- methoxypropan-2-yl)-5-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl)pyrimidine-2,4- diamine

¹H-NMR (Bruker, 500 MHz, MeOD) δ 7.98 (s, 1 H), 4.54- 4.58 (m, 1 H),3.60-3.72 (m, 2 H), 3.342 (s, 3 H), 2.96 (s, 3 H), 2.23 (s, 3 H), 1.45(d, J = 6.5, 3 H). 0.019 206 N4-methyl-N2-(4- methyl-1H-pyrazol-5-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1 H), 7.33 (s, 1 H), 5.33 (s, 1 H),3.08 (d, J = 4.8, 3 H), 2.05 (s, 3 H). 273 0.2324 207 N4-ethyl-N2-(5-methyl-1-(1- methylpiperidin-4- yl)-1H-pyrazol-4- yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.80 (s, 1 H), 8.04 (s, 1 H), 7.61 (s, 1 H),6.90 (s, 1 H), 4.02 (m, 1 H), 3.39 (m, 2 H), 2.93-2.76 (m, 2 H), 2.20(m, 6 H), 2.10-1.93 (m, 4 H), 1.75 (m, 2 H), 1.07 (m, 3 H). 0.0026 208N4-ethyl-N2-(3- methyl-1-(1- methylpiperidin-4- yl)-1H-pyrazol-4- yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.90 (s, 1 H), 8.08 (s, 1 H), 7.88 (s, 1 H),7.02 (s, 1 H), 4.01-3.83 (m, 1 H), 3.43 (s, 2 H), 2.82 (d, J = 11.6, 2H), 2.16-1.76 (m, 9 H), 1.12 (t, J = 7.0, 3 H). 0.0102 209N4-methyl-N2-(3- methyl-1-(1- methylpiperidin-4- yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

370.2 0.041 210 N4-methyl-N2-(5- methyl-1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

370.2 0.0071 211 (R)-N4-methyl- N2-(5-methyl-1-(1- (oxetan-3-yl)pyrrolidin-3-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 9.00 (s, 1 H), 8.12 (d, J = 18, 1 H), 7.85 (s,1 H), 7.05 (s, 1 H), 4.77-4.80 (m, 1 H), 4.46- 4.59 (m, 2 H), 4.43-4.48(m, 2 H), 3.62 (t, J = 5.5, 1 H), 2.93 (s, 3 H), 2.76 (s, 3 H), 2.44 (s,1 H), 2.36 (t, J = 2, 1 H), 1.99-2.15 (m, 4 H). 0.0033 212N4-methyl-N2-(5- methyl-1-(pyridin- 2-ylmethyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.57 (d, J = 5, 8.11 (s, 1 H), 7.97 (s, 1 H),7.62-7.66 (m, 1 H), 7.21 (t, J = 1.5, 1 H), 7.04 (d, J = 8, 1 H), 6.62(s, 1 H), 5.37 (s, 2 H), 5.16 (d, J = 4.5, 1 H), 2.98 (s, 3 H), 2.29 (s,3 H). 0.0029 213 N4-methyl-N2-(3- methyl-1-(pyridin- 2-ylmethyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 8.56 (d, J = 4.5 Hz), 8.09 (s, 1 H), 7.82-7.85(m, 1 H), 7.60- 7.64 (m, 1 H), 7.19-7.21 (m, 1 H), 7.89 (3, 1 H), 6.62(s, 1 H), 5.42 (s, 2 H), 5.14 (s, 1 H), 2.98 (d, J = 4, 3 H), 2.18 (s, 3H). 0.0029 214 N2-(1-(1- isopropylazetidin- 3-yl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.91 (s, 1 H), 8.05 (s, 1 H), 7.78 (s, 1 H),6.93 (s, 1 H), 4.82 (dd, J = 14.4, 7.2, 1 H), 3.64 (t, J = 7.2, 2 H),2.84 (s, 2 H), 2.36 (dt, J = 12.4, 6.2, 1 H), 2.16 (s, 3 H). 0.064 2151-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazole-5- carbonitrile

1H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1 H), 8.14 (s, 1 H), 7.20 (br s, 1H), 5.29 (s, 1 H), 4.01 (s, 3 H), 3.09 (d, J = 4.7, 3 H). 298 0.0032 216N4-ethyl-N2-(1- (isopropylsulfonyl)- 3-methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.41 (s, 1 H), 8.44 (s, 1 H), 8.19 (s, 1 H),7.26 (s, 1 H), 3.76 (m, 1 H), 3.54-3.39 (m, 2 H), 2.31 (s, 3 H),1.24-1.10 (m, 10 H). 0.0039 217 N2-(1- (isopropylsulfonyl)- 3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.39 (s, 1 H), 8.47 (s, 1 H), 8.20 (s, 1 H),7.20 (s, 1 H), 3.77 (dq, J = 13.6, 6.8, 1 H), 2.90 (d, J = 4.4, 3 H),2.31 (s, 3 H), 1.19 (d, J = 6.8, 6 H). 0.0099 218 N2-(1-(isopropylsulfonyl)- 5-methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.08 (s, 1 H), 8.14 (d, J = 21.1, 2 H), 7.06(s, 1 H), 3.85-3.74 (m, 1 H), 2.82 (s, 3 H), 2.39 (s, 3 H), 1.20 (d, J =6.8, 6 H). 0.0081 219 N2-(1-(sec- butylsulfonyl)-5- methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.08 (s, 1 H), 8.13 (d, J = 14.5, 2 H), 7.06(s, 1 H), 3.70-3.57 (m, 1 H), 2.82 (s, 3 H), 1.84-1.69 (m, 1 H), 1.56-1.41 (m, 1 H), 1.16 (d, J = 6.8, 3 H), 0.93 (t, J = 7.5, 3 H). 0.0067220 N2-(1-(sec- butylsulfonyl)-3- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.39 (s, 1 H), 8.47 (s, 1 H), 8.19 (s, 1 H),7.20 (s, 1 H), 3.60 (dq, J = 13.7, 6.9, 1 H), 2.90 (d, J = 4.3, 3 H),2.31 (s, 3 H), 1.87-1.70 (m, 1 H), 1.45 (dt, J = 14.0, 7.7, 1 H), 1.16(d, J = 6.9, 3 H), 0.92 (t, J = 7.5, 3 H). 0.0117 221 1-(4-(4-(ethylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-3- isopropyl-1H-pyrazol-l-yl)-2- methylpropan-2-ol

0.0061 222 N2-(1-(3-fluoro-1- methylpiperidin-4- yl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.05 (s, 1 H), 7.78 (s, 1 H),6.93 (s, 1 H), 4.91 (m, 1 H), 4.77 (m, 1 H), 4.35-4.05 (m, 1 H), 3.26-3.10 (m, 1 H), 2.83 (s, 4 H), 2.28 (m, 3 H), 2.26-2.00 (m, 5 H), 1.86(m, 1 H). 0.0016 223 N2-(5-isopropyl-1- methyl-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

315.1 0.014 224 N4-methyl-N2-(3- methyl-1-(1- (pyridin-2- yl)ethyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H-NMR (500 MHz, CDCl₃) δ 8.54 (d, J = 4.0, 1 H), 7.97- 8.12 (m, 2 H),7.78-7.81 (m, 1 H), 7.32-7.35 (m, 1 H), 7.12 (d, J = 7.5, 1 H),5.53-5.57 (m, 1 H), 5.90-5.91 (m, 3 H), 2.23 (s, 3 H), 1.91 (d, J = 7.0,3 H). 0.0024 225 N4-methyl-N2-(5- methyl-1-(1- (pyridin-2- yl)ethyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H-NMR (500 MHz, CDCl₃) δ 8.53 (t, J = 4.0, 1 H), 7.98 (s, 1 H),7.72-7.78 (m, 2 H), 7.31-7.34 (m, 1 H), 6.96 (s, 1 H), 5.62-5.67 (m, 1H), 2.86- 2.96 (m, 3 H), 2.15 (s, 3 H), 1.95 (d, J = 7.5, 3 H). 0.0038226 N2-(5-chloro-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.91 (s, 1 H), 8.08 (s, 1 H), 7.82 (s, 1 H),7.00 (s, 1 H), 4.50 (tt, J = 11.4, 4.3, 1 H), 3.97 (dd, J = 11.3, 4.0, 2H), 3.49 (t, J = 11.4, 2 H), 2.83 (s, 3 H), 2.01 (qd, J = 12.4, 4.6, 2H), 1.81 (dd, J = 12.8, 2.4, 2 H). 0.0007 227 N2-(3-isopropyl-1-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

315.1 0.069 228 N2-(3-cyclobutyl- 1-methyl-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

327.1 0.0034 229 N2-(5-cyclobutyl- 1-methyl-1H- pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.21-7.98 (s, 1 H), 7.82- 7.34 (s, 1 H), 6.58-6.18 (s, 1 H), 5.22-5.01 (s, 1 H), 3.82-3.70 (s, 3 H), 3.67-3.50 (m, 1H), 3.06- 2.94 (d, J = 4.7 Hz, 3 H), 2.54- 2.26 (m, 4 H), 2.16-1.99 (m,1 H), 1.97- 1.81 (m, 1 H) 327.1 0.011 230 N4-methyl-N2-(3- methyl-1-(tetrahydro-2H- pyran-3-yl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.95 (s, 1 H), 8.08 (s, 2 H), 6.98 (s, 1 H),4.22-4.07 (m, 1 H), 3.92 (dd, J = 10.9, 3.6, 1 H), 3.77 (d, J = 11.1, 1H), 3.55 (t, J = 9.8, 1 H), 3.41 (t, J = 9.7, 1 H), 2.89 (d, J = 4.4, 3H), 2.21-1.92 (m, 5 H), 1.79-1.53 (m, 2 H). 0.0096 231 N4-methyl-N2-(5-methyl-1- (tetrahydro-2H- pyran-3-yl)-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.89 (s, 1 H), 8.05 (s, 1 H), 7.73 (s, 1 H),6.92 (s, 1 H), 4.26-4.11 (m, 1 H), 3.86 (dd, J = 10.7, 2.4, 2 H), 3.51(t, J = 10.6, 1 H), 2.83 (s, 3 H), 2.21 (s, 3 H), 2.12-1.94 (m, 2 H),1.85-1.58 (m, 2 H). 0.0018 232 N2-(1,5-dimethyl- 1H-pyrazol-4-yl)-N4-((tetrahydro- 2H-pyran-4-yl) methyl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

0.0096 233 (R)-N4-methyl- N2-(3-methyl-1-(1- methylpyrrolidin-3-yl)-1H-pyrazol- 4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

¹H NMR (500 MHz, DMSO) δ 9.00 (s, 1 H), 8.13 (s, 1 H), 8.08 (s, 1H ),7.03 (s, 1 H), 4.74 (m, 1 H), 2.90 (d, J = 4.5 Hz, 3 H), 2.75-2.80 (m, 3H), 2.30 (m, 5 H), 2.14 (s, 3 H), 1.96 (s, 2 H). 0.061 2341-(5-chloro-4-(4- (ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1-yl)-2- methylpropan-2-ol

1H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1 H), 8.02 (s, 1 H), 6.81 (br s, 1H), 5.62 (br s, 1 H), 4.10 (s, 2 H), 3.84 (s, 1 H), 3.59 (p, J = 6.6, 2H), 1.31 (t, J = 7.2, 3 H), 1.19 (s, 6 H). 379 0.0031 2351-(3-cyclopropyl- 4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1-yl)-2- methylpropan-2-ol

1H NMR (400 MHz, CDCl₃) δ 8.18-8.09 (s, 1 H), 7.93- 7.82 (s, 1 H),3.98-3.92 (s, 2 H), 3.10-3.01 (d, J = 4.7 Hz, 3 H), 1.80-1.68 (td, J =8.3, 4.2 Hz, 1 H), 1.19-1.09 (s, 6 H), 0.98-0.77 (m, 4 H) 371.2 0.0051236 1-(3-cyclopropyl- 4-(4-(ethylamino)- 5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropan-2-ol

1H NMR (400 MHz, CDCl₃) δ 8.15-8.10 (s, 1 H), 7.86- 7.81 (s, 1 H),3.95-3.92 (s, 2 H), 3.59-3.49 (m, 2 H), 1.77-1.67 (td, J = 8.3, 4.1 Hz,1 H), 1.32-1.23 (t, J = 7.2 Hz, 3 H), 1.18-1.12 (s, 6 H), 0.95-0.75 (m,4 H) 385.2 0.0015 237 2-(5-chloro-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-N,2-dimethylpropan- amide

1H NMR (400 MHz, DMSO) δ 8.90 (s, 1 H), 8.09 (s, 1 H), 7.85 (s, 1 H),7.67 (d, J = 4.4, 1 H), 7.02 (s, 1 H), 2.84 (d, J = 3.8, 3 H), 2.60 (d,J = 4.5, 3 H), 1.66 (s, 6 H). 0.045 238 N2-(1-(1-(2- methoxyethyl)piperidin-4-yl)-3- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.07 (s, 1 H), 7.94 (s, 1 H),6.97 (s, 1 H), 3.95 (dt, J = 15.5, 5.6, 1 H), 3.43 (t, J = 5.8, 2 H),3.24 (s, 3 H), 2.93 (d, J = 11.8, 2 H), 2.88 (d, J = 4.4, 3 H), 2.10 (d,J = 11.8, 5 H), 2.02-1.72 (m, 4 H). 0.016 239 N2-(1-(1-(2- methoxyethyl)piperidin-4-yl)-5- methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.86 (s, 1 H), 8.04 (s, 1 H), 7.71 (s, 1 H),6.91 (s, 1 H), 4.12-3.88 (m, 1 H), 3.44 (t, J = 5.9, 2 H), 3.24 (s, 3H), 2.96 (d, J = 11.6, 2 H), 2.84 (s, 3 H), 2.15 (dd, J = 22.8, 10.9, 4H), 1.98 (qd, J = 12.2, 3.4, 2 H), 1.75 (d, J = 12.3, 2 H). 0.006 240(R)-N4-methyl- N2-(5-methyl-1-(1- methylpyrrolidin- 3-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidine-2,4- diamine

241 N2-(5-chloro-1-(3- fluoro-1- methylpiperidin-4- yl)-1H-pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.94 (s, 1 H), 8.08 (s, 1 H), 7.85 (s, 1 H),7.00 (s, 1 H), 4.87 (dtd, J = 49.9, 9.8, 5.1, 1 H), 4.34 (qd, J = 11.2,4.9, 1 H), 3.27-3.15 (m, 1 H), 2.82 (s, 4 H), 2.22-2.04 (m, 3 H), 1.91(s, 1 H). 0.0018 242 N2-(5-chloro-1-(1- ethyl-3- fluoropiperidin-4-yl)-1H-pyrazol-4- yl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.95 (s, 1 H), 8.08 (s, 1 H), 7.87 (s, 1 H),7.00 (s, 1 H), 4.86 (m, 1 H), 4.36 (m, 1 H), 3.08-2.71 (m, 4 H), 2.25-1.81 (m, 5 H), 1.03 (t, J = 7.1, 3 H). 0.0021 243 N4-ethyl-N2-(1-(ethylsulfonyl)-3- methyl-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.40 (s, 1 H), 8.45 (s, 1 H), 8.20 (s, 1 H),7.28 (s, 1 H), 3.58 (q, J = 7.3, 2 H), 3.53- 3.37 (m, 2 H), 2.31 (s, 3H), 1.16 (t, J = 7.0, 3 H), 1.07 (t, J = 7.3, 3 H). 0.0005 244N4-ethyl-N2-(1- (ethylsulfonyl)-5- methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.07 (s, 1 H), 8.11 (s, 2 H), 7.05 (s, 1 H),3.62 (q, J = 7.3, 2 H), 3.37 (s, 2 H), 2.39 (s, 3 H), 1.09 (t, J = 7.3,6 H). 0.0047 245 N4-methyl-N2-(3- methyl-1-(2- methyl-2-morpholinopropyl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

414.2 246 N2-(1-(1-ethyl-3- fluoropiperidin-4- yl)-3-methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.05 (s, 1 H), 7.79 (s, 1 H),6.95 (s, 1 H), 5.22-4.55 (m, 1 H), 4.22 (dd, J = 21.0, 11.1, 1 H), 2.85(d, J = 21.1, 3 H), 2.33-1.97 (m, 5 H), 1.03 (t, J = 7.1, 3 H). 402.2247 N2-(5- (dimethylamino)- 1-methyl-1H- pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

1H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1 H), 7.74 (br s, 1 H), 6.52 (br s, 1H), 5.13 (s, 1 H), 3.74 (s, 3 H), 3.02 (d, J = 4.7, 3 H), 2.80 (s, 6 H).316 0.0779 248 2-(5-chloro-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropan-1-ol

1H NMR (400 MHz, DMSO) δ 8.75 (s, 1 H), 8.08 (s, 1 H), 7.73 (s, 1 H),6.99 (s, 1 H), 4.92 (t, J = 5.7, 1 H), 3.77 (d, J = 5.6, 2 H), 2.83 (d,J = 3.0, 3 H), 1.57 (s, 6 H). 365.1 249 N²-(1- (ethylsulfonyl)-3-methyl-1H- pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 9.41 (s, 1 H), 8.48 (s, 1 H), 8.20 (s, 1 H),7.20 (s, 1 H), 3.58 (q, J = 7.3, 2 H), 2.91 (d, J = 4.4, 3 H), 2.31 (s,3 H), 1.08 (t, J = 7.3, 3 H). 365.1 0.0033 250 2-Methyl-1-[3-methyl-4-(4- methylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-pyrazol- 1-yl]-propan-2-ol

0.0122 251 N2-[1-(2-Methoxy- ethyl)-3-methyl- 1H-pyrazol-4-yl]-N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0026 252 N2-[1-(2-Methoxy- ethyl)-5-methyl- 1H-pyrazol-4-yl]-N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0061 253 5-Bromo-N2-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-N4-methyl-pyrimidine- 2,4-diamine

0.0022 254 N4-Methyl-N2-[3- methyl-1-(2,2,2- trifluoro-ethyl)-1H-pyrazol-4-yl]- 5-trifluoromethyl- pyrimidine-2,4- diamine

0.0077 255 5-Bromo-N2-(1- difluoromethyl-5- methyl-1H- pyrazol-4-yl)-N4-methyl-pyrimidine- 2,4-diamine

0.0007 256 5-Bromo-N2-(1- difluoromethyl-3- methyl-1H- pyrazol-4-yl)-N4-methyl-pyrimidine- 2,4-diamine

0.0022 257 5-Bromo-N2-(1,5- dimethyl-1H- pyrazol-4-yl)-N4-ethyl-pyrimidine- 2,4-diamine

0.0015 258 5-Bromo-N2-[1-(4- fluoro-phenyl)-5- methyl-1H-pyrazol-4-yl]-N4- methyl-pyrimidine- 2,4-diamine

259 5-Bromo-N4- methyl-N2-(5- methyl-1-propyl- 1H-pyrazol-4-yl)-pyrimidine-2,4- diamine

0.0057 260 5-Bromo-N2-[1-(4- chloro-phenyl)-3- methyl-1H-pyrazol-4-yl]-N4- methyl-pyrimidine- 2,4-diamine

0.0003 261 N2-(1,5-Dimethyl- 1H-pyrazol-4-yl)- N4-ethyl-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0013 262 5-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-piperidin-2-one

0.0013 263 4-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-N,N-dimethyl- benzamide

0.0018 264 N2-[1-(4- Cyclopropane- sulfonyl-phenyl)-3- methyl-1H-pyrazol-4-yl]-N4- ethyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0032 265 4-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-benzonitrile

0.0048 266 N4-Ethyl-N2-[1- (4- methanesulfonyl- phenyl)-3-methyl-1H-pyrazol-4-yl]- 5-trifluoromethyl- pyrimidine-2,4- diamine

0.0021 267 1-{4-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-5- methyl-pyrazol-1- yl]-piperidin-1-yl}- 2-methyl-propan-1-one

0.0008 268 1-{4-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-piperidin-1-yl}- 2-methyl-propan-1-one

0.0077 269 N4-Methyl-N2-[3- methyl-1-(3- methyl-pyridin-4-yl)-1H-pyrazol-4- yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0091 270 N2-[1-((R)-2- Methoxy-propyl)- 3-methyl-1H- pyrazol-4-yl]-N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.017 272 N2-[1-(2,6- Dimethyl- tetrahydro-pyran- 4-yl)-5-methyl-1H-pyrazol-4-yl]-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0051 273 N2-[1-(1,1-Dioxo- hexahydro- 1$1%6&- thiopyran-4-yl)-3-methyl-1H- pyrazol-4-yl]-N4- mcthyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.037 274 N2-[1-((R)-2- Methoxy-1- methyl-ethyl)-5- methyl-1H-pyrazol-4-yl]-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0185 275 N2-[1-((S)-2- Methoxy-1- methyl-ethyl)-3- methyl-1H-pyrazol-4-yl]-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0089 276 N4-Methyl-N2-[3- methyl-1-((S)-1- oxetan-3-yl-pyrrolidin-3-yl)- 1H-pyrazol-4-yl]- 5-trifluoromethyl- pyrimidine-2,4-diamine

0.0039 277 N4-Methyl-N2-[5- methyl-1-((S)-1- oxetan-3-yl-pyrrolidin-3-yl)- 1H-pyrazol-4-yl]- 5-trifluoromethyl- pyrimidine-2,4-diamine

0.058 278 N2-[1-(1- Isopropyl-azetidin- 3-yl)-5-methyl-1H-pyrazol-4-yl]-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0012 279 N4-Ethyl-N2-[5- methyl-1-(propane- 2-sulfonyl)-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0047 280 N2-(5-Cyclobutyl- 1-methyl-1H- pyrazol-4-yl)-N4- ethyl-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0036 281 N2-(3-Cyclobutyl- 1-methyl-1H- pyrazol-4-yl)-N4- ethyl-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0013 282 N4-Ethyl-N2-{1- [1-(2-methoxy- ethyl)-piperidin-4-yl]-3-methyl-1H- pyrazol-4-yl}-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0054 283 N4-Ethyl-N2-{1- [1-(2-methoxy- ethyl)-piperidin-4-yl]-5-methyl-1H- pyrazol-4-yl}-5- trifluoromethyl- pyrimidine-2,4-diamine

0.002 284 N2-{1-[1-(2- Fluoro-ethyl)- piperidin-4-yl]-5- methyl-1H-pyrazol-4-yl}-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0042 285 N2-{1-[1-(2- Fluoro-ethyl)- piperidin-4-yl]-3- methyl-1H-pyrazol-4-yl}-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0283 286 N2-[5-Chloro-1-(3- fluoro-1-methyl- piperidin-4-yl)-1H-pyrazol-4-yl]-N4- methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.95 (s, 1 H), 8.08 (s, 1 H), 7.88 (s, 1 H),7.00 (s, 1 H), 4.87 (dtd, J = 49.9, 9.8, 5.1, 1 H), 4.34 (qd, J = 11.3,4.9, 1 H), 3.29-3.13 (m, 1 H), 2.82 (s, 4 H), 2.28 (s, 3 H), 2.25-1.99(m, 3 H), 1.92 (d, J = 6.8, 1 H). 0.0018 287 N2-(1- Ethanesulfonyl-5-methyl-1H- pyrazol-4-yl)-N4- methyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0072 288 N4-Methyl-N2-[5- methyl-1-(2- methyl-2- morpholin-4-yl-propyl)-1H- pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0077 289 N4-Methyl-N2-(3- methyl-1-pyridin- 3-ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.025 290 N2-(1- Cyclopropane- sulfonyl-3- cyclopropyl-1H-pyrazol-4-yl)- N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

291 N4-Methyl-N2-(5- methyl-1-pyridin- 3-ylmethyl-1H- pyrazol-4-yl)-5-trifluoromethyl- pyrimidine-2,4- diamine

292 (5-Chloro-4- methoxy- pyrimidin-2-yl)-{1- [1-(2-fluoro-ethyl)-piperidin-4-yl]-5- methyl-1H- pyrazol-4-yl}- amine

0.0042 293 N4-Methyl-N2-[3- methyl-1-(6- methyl-pyridin-2- ylmethyl)-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0006 294 N4-Ethyl-N2-[1- (2-methoxy-ethyl)- 3-methyl-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0011 295 N4-Ethyl-N2-[1- (2-methoxy-ethyl)- 5-methyl-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0004 296 1-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-5- methyl-pyrazol-1- yl]-2-methyl- propan-2-ol

1H NMR (400 MHz, DMSO) δ 8.75 (s, 1 H), 8.05 (s, 1 H), 7.57 (s, 1 H),6.86 (s, 1 H), 4.63 (s, 1 H), 3.90 (s, 2 H), 3.36 (s, 2 H), 2.19 (s, 3H), 1.08 (s, 7 H). 0.0023 297 1-[4-(4- Ethylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-3- methyl-pyrazol-1- yl]-2-methyl- propan-2-ol

1H NMR (400 MHz, DMSO) δ 8.83 (s, 1 H), 8.07 (s, 1 H), 7.85 (s, 1 H),6.91 (s, 1 H), 4.60 (s, 1 H), 3.79 (d, J = 64.3, 2 H), 3.42 (s, 2 H),2.27-1.82 (m, 3 H), 1.35-1.05 (m, 3 H), 0.97 (d, J = 63.4, 6 H). 0.0021298 N2-[1-(1,1- Dimethyl-2- morpholin-4-yl- ethyl)-3-methyl-1H-pyrazol-4-yl]- N4-ethyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0506 299 N2-[1-(1,1- Dimethyl-2- morpholin-4-yl- ethyl)-3-methyl-1H-pyrazol-4-yl]- N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0228 300 N4-Cyclopropyl- N2-(1- methanesulfonyl-3- methyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.55 (s, 1 H), 8.83 (s, 1 H), 8.22 (s, 1 H),7.27 (s, 1 H), 3.39 (s, 3 H), 2.79 (s, 1 H), 2.34 (s, 3 H), 0.95-0.58(m, 4 H). 0.0004 301 N4-Cyclopropyl- N2-(1- methanesulfonyl-5-methyl-1H- pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 9.25 (s, 1 H), 8.40 (s, 1 H), 8.14 (s, 1 H),7.04 (s, 1 H), 3.46 (s, 3 H), 2.79 (s, 1 H), 2.43 (s, 3 H), 0.68 (dd, J= 13.9, 9.3, 4 H). 0.0021 302 1-[3-Chloro-4-(4- methylamino-5-trifluoromethyl- pyrimidin-2- ylamino)-pyrazol- 1-yl]-2-methyl-propan-2-ol

0.016 303 2-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-N-methyl- isobutyramide

0.0013 304 N4-Methyl-N2-(3- methyl-1- pyrimidin-2- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0051 305 N2-[5-Chloro-1-(3- fluoro-1-oxetan-3- yl-piperidin-4-yl)-1H-pyrazol-4-yl]- N4-methyl-5- trifluoromethyl- pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.91 (s, 1 H), 8.08 (s, 1 H), 7.86 (s, 1 H),7.00 (s, 1 H), 4.97 (td, J = 9.8, 5.0, 0 H), 4.90-4.74 (m, 1 H), 4.63-4.52 (m, 2 H), 4.46 (dt, J = 21.3, 7.5, 3 H), 3.71-3.53 (m, 1 H),3.26-3.11 (m, 1 H), 2.94-2.71 (m, 4 H), 2.16- 1.85 (m, 4 H). 0.0022 306N2-[5-Chloro-1-(3- fluoro-1-oxetan-3- yl-piperidin-4-yl)-1H-pyrazol-4-yl]- N4-ethyl-5- trifluoromethyl- pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 8.84 (s, 1 H), 8.08 (s, 1 H), 7.80 (s, 1 H),6.98 (s, 1 H), 5.02-4.79 (m, 1 H), 4.56 (t, J = 6.5, 3 H), 4.46 (dt, J =20.4, 7.0, 4 H), 3.65-3.53 (m, 2 H), 3.24-3.15 (m, 1 H), 2.77 (s, 1 H),2.20-1.85 (m, 5 H), 1.05 (s, 4 H). 0.0006 307 N4-Ethyl-N2-[5-methyl-1-((S)-1- oxetan-3-yl- piperidin-3-yl)-1H- pyrazol-4-yl]-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0003 308 N4-Ethyl-N2-[3- methyl-1-((S)-1- oxetan-3-yl-piperidin-3-yl)-1H- pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0085 309 N4-Methyl-N2-(5- methyl-1- pyridazin-3- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0028 310 N4-Methyl-N2-(3- methyl-1- pyridazin-3- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0093 311 N4-Ethyl-N2-[5- methyl-1-((S)-1- methyl-piperidin-3-yl)-1H-pyrazol- 4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0012 312 N4-Ethyl-N2-[3- methyl-1-((S)-1- methyl-piperidin-3-yl)-1H-pyrazol- 4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0156 313 3-[5-Chloro-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]-2,2-dimethyl- propionitrile

1H NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.09 (s, 1 H), 7.86 (s, 1 H),7.00 (s, 1 H), 4.29 (s, 2 H), 2.82 (s, 3 H), 1.38 (s, 6 H). 0.0017 314N4-Methyl-N2-[5- methyl-1-(6- methyl-pyridin-2- ylmethyl)-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0015 315 N4-Methyl-N2-(5- methyl-1- pyrimidin-2- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0014 316 N4-Methyl-N2-(5- methyl-1-pyrazin- 2-ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0026 317 N4-Methyl-N2-(3- methyl-1-pyrazin- 2-ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0012 318 3-[5-Chloro-4-(4- ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-pyrazol- 1-yl]-2,2-dimethyl- propionitrile

1H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.09 (s, 1 H), 7.80 (s, 1 H),6.98 (s, 1 H), 4.30 (s, 2 H), 3.35 (s, 2 H), 1.38 (s, 6 H), 1.05 (s, 3H). 0.0007 319 N4-Ethyl-N2-[1- (3-fluoro-1-oxetan- 3-yl-piperidin-4-yl)-3-methyl-1H- pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4-diamine

1H NMR (400 MHz, DMSO) δ 8.79 (s, 1 H), 8.05 (s, 1 H), 7.67 (s, 1 H),6.87 (s, 1 H), 5.06-4.73 (m, 1 H), 4.56 (td, J = 6.5, 2.5, 2 H), 4.46(dt, J = 12.0, 6.1, 2 H), 4.26 (dd, J = 21.1, 11.2, 1 H), 3.58 (p, J =6.3, 1 H), 3.38 (s, 2 H), 3.22- 3.07 (m, 1 H), 2.77 (d, J = 9.0, 1 H),2.26 -1.99 (m, 6 H), 1.90 (s, 1 H), 1.08 (s, 3 H). 0.0003 3203-Methyl-1-[5- methyl-4-(4- methylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-pyrazol- 1-yl]-butan-2-ol

1H NMR (400 MHz, DMSO) δ 8.82 (s, 1 H), 8.04 (s, 1 H), 7.65 (s, 1 H),6.88 (s, 1 H), 4.71 (d, J = 5.2, 1 H), 3.93 (ddd, J = 21.6, 14.0, 6.1, 2H), 3.59 (dd, J = 7.4, 4.5, 1 H), 2.83 (s, 3 H), 2.19 (s, 3 H), 1.58(dd, J = 12.0, 6.5, 1 H), 0.90 (t, J = 7.0, 6 H). 0.0030 3213-Methyl-1-[3- methyl-4-(4- methylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-pyrazol- 1-yl]-butan-2-ol

0.0108 322 N2-[1-(1- [1,3]Dioxolan-2- ylmethyl- pyrrolidin-3-yl)-3-methyl-1H- pyrazol-4-yl]-N4- ethyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0049 323 N4-Methyl-N2-(5- methyl-1- pyrimidin-4- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0022 324 N4-Methyl-N2-[5- methyl-1-(1- methyl-1H- pyrazol-3-ylmethyl)-1H- pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0006 325 N4-Methyl-N2-[3- methyl-1-(1- methyl-1H- pyrazol-3-ylmethyl)-1H- pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0038 326 3-[3-Chloro-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]-2,2-dimethyl- propionitrile

0.0082 327 N4-Ethyl-N2-{3- methyl-1-[1- methyl-1-(4H-[1,2,4]triazol-3-yl)- ethyl]-1H-pyrazol- 4-yl}-5- trifluoromethyl-pyrimidine-2,4- diamine

0.0005 328 N2-[1-(1- [1,3]Dioxolan-2- ylmethyl- pyrrolidin-3-yl)-5-methyl-1H- pyrazol-4-yl]-N4- ethyl-5- trifluoromethyl- pyrimidine-2,4-diamine

0.0004 329 N4-Methyl-N2-(3- methyl-1- pyrimidin-4- ylmethyl-1H-pyrazol-4-yl)-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0052 330 N2-(5- Fluoromethyl-1- methyl-1H- pyrazol-4-yl)-N4- methyl-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0245 331 N4-Ethyl-N2-{3- methyl-1-[1- methyl-1-(5- methyl-4H-[1,2,4]triazol-3-yl)- ethyl]-1H-pyrazol- 4-yl}-5- trifluoromethyl-pyrimidine-2,4- diamine

1H NMR (400 MHz, DMSO) δ 13.49 (d, J = 53.3, 1 H), 8.89 (s, 1 H), 8.07(s, 1 H), 7.78 (s, 1 H), 6.96 (s, 1H ), 2.31 (s, 3 H), 2.13 (s, 3 H),1.83 (s, 6 H), 1.06 (s, 3 H). 0.0008 332 N4-Methyl-N2-{3- methyl-1-[1-methyl-1-(4H- [1,2,4]triazol-3-yl)- ethyl]-1H-pyrazol- 4-yl}-5-trifluoromethyl- pyrimidine-2,4- diamine

0.0023 333 N4-Ethyl-N2-[1- (3-fluoro- piperidin-4-yl)-3- methyl-1H-pyrazol-4-yl]-5- trifluoromethyl- pyrimidine-2,4- diamine

0.0007 334 2-[5-Methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- cyclopentanol

0.0063 335 2-[3-Methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- cyclopentanol

0.0033 336 N4-ethyl-N2-(3- methyl-1-(2-(5- methyl-1,3,4- oxadiazol-2-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluorometliyl) pyrimidine-2,4-diamine

0.0012 337 N4-ethyl-N2-(3- methyl-1-(2-(4- methyl-4H-1,2,4- triazol-3-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0076 338 N4-ethyl-N2-(3- methyl-1-(2-(1- methyl-1H-1,2,4- triazol-3-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0003 339 N4-methyl-N2-(3- methyl-1-(2-(5- methyl-1,3,4- oxadiazol-2-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0117 340 N4-methyl-N2-(3- methyl-1-(2-(1- methyl-1H- pyrazol-4-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0003 341 N4-methyl-N2-(5- methyl-1-(2-(1- methyl-1H- pyrazol-4-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0061 342 N4-ethyl-N2-(3- methyl-1-(2-(1- methyl-1H- pyrazol-3-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0217 343 N4-ethyl-N2-(3- methyl-1-(2-(1- methyl-1H- pyrazol-5-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0003 344 N4-methyl-N2-(3- methyl-1-(2-(1- methyl-1H- pyrazol-5-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.0014 345 N4-methyl-N2-(3- methyl-1-(2-(1- methyl-1H- pyrazol-3-yl)propan-2-yl)- 1H-pyrazol-4-yl)- 5-(trifluoromethyl) pyrimidine-2,4-diamine

0.115 346 N2-(1′,5-dimethyl- 1′H-1,4′-bipyrazol- 4-yl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

347 N2-(1′,3-dimethyl- 1′H-1,4′-bipyrazol- 4-yl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4- diamine

348 N2-(1-(2-(4H- 1,2,4-triazol-3- yl)propan-2-yl)-3- methyl-1H-pyrazol-4-yl)-N4- methyl-5- (trifluoromethyl) pyrimidine-2,4- diamine

Example 3492-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile

To a mixture of5-bromo-N²-(1,5-dimethyl-1H-pyrazol-4-yl)-N⁴-methylpyrimidine-2,4-diamine(95 mg, 0.32 mmol), zinc cyanide (70 mg, 0.60 mmol), Pd₂(dba)₃ (11 mg,0.012 mmol), DPPF (13 mg, 0.023 mmol) was added DMF (3.5 mL). Thereaction was then heated in a sealed tube at 105° C. for 18 h. Thereaction mixture was filtered and concentrated. The crude product waspurified by reverse phase HPLC to give2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile(19 mg, 25%). LCMS (Method A): [MH⁺]=244.1 at 2.53 min. ¹H-NMR (DMSO): δ8.96 (m, 1H), 8.21 (m, 1H), 7.49 (m, 2H), 3.69 (s, 3H), 2.84 (m, 3H),2.14 (m, 3H). K₁=0.025.

Compounds made using the above procedure are shown in Table 9 below,together with low resolution mass spectrometry (M+H), proton NMR, andLRRK2 K_(i) (micromolar) data for selected compounds determined from theassay described below.

TABLE 9 Name Structure ¹H NMR M + H⁺ K_(I) 350 2-(1,3-Dimethyl-1H-pyrazol-4- ylamino)-4- methylamino- pyrimidine-5- carbonitrile

¹H-NMR (DMSO): δ 9.15 (s, 1H), 8.23 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H),3.72 (s, 3H), 2.86 (d, J = 4.4, 3H), 2.12 (s, 3H). 244.1 0.029 3512-(1-ethyl-5- methyl-1H- pyrazol-4- ylamino)-4- (methylamino)pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 8.21 (s, 1H), 7.73-7.27 (m, 2H),4.01 (q, J = 7.2, 2H), 2.80 (m, 3H), 2.20 (m, 3H), 1.27 (t, J = 7.2,3H). 0.0097 352 2-(1-isopropyl-3- methyl-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.55(s, 1H), 4.35 (m, 1H), 2.86 (d, J = 4.5, 3H), 2.14 (m, 3H), 1.36 (d, J =6.6, 6H). 0.048 353 2-(1-ethyl-3- methyl-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 8.10 (s, 0H), 7.58 (d, J = 2.1, 0H), 7.01 (d, J= 3.6, 0H), 6.60 (s, 0H), 4.02 (q, J = 7.2, 1H), 2.91 (d, J = 4.4, 1H),1.35 (t, J = 7.2, 1H). 0.036 354 2-(3-methyl-1- phenyl-1H- pyrazol-4-ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.71(d, J = 8.0, 2H), 7.46 (t, J = 7.9, 2H), 7.24 (t, J = 7.4, 1H), 2.92 (d,J = 3.5, 3H), 2.27 (s, 3H). 0.12 355 2-(3-methyl-1-(1- (2,2,2-trifluoroethyl) piperidin-4-yl)-1H- pyrazol-4- ylamino)-4- (methylamino)pyrimidine-5- carbonitrile

0.299 356 2-(5-methyl-1-(1- (2,2,2- trifluoroethyl) piperidin-4-yl)-1H-pyrazol-4- ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

0.0225 357 2-(1-methyl-1H- pyrazol-4- ylamino)-4- (methylamino)pyrimidine-5- carbonitrile

358 2-(5-methyl-1- (2,2,2- trifluoroethyl)-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 7.53(s, 1H), 5.02 (q, J = 9.2, 2H), 2.79 (s, 3H), 2.23 (s, 3H). 0.032 3592-(3-methyl-1- (2,2,2- trifluoroethyl)-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.59(s, 1H), 5.00 (q, J = 9.0, 2H), 2.86 (d, J = 4.0, 3H), 2.17 (s, 3H).0.053 360 2-(5-methyl-1- phenyl-1H- pyrazol-4- ylamino)-4- (methylamino)pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 116.0,1H), 7.46 (d, J = 37.7, 6H), 2.86 (s, 3H), 2.28 (s, 3H). 0.0013 3612-(5-methyl-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 8.96 (d, J = 136.9, 1H), 8.20 (d, J = 5.4, 1H),7.73 (s, 1H), 7.44 (d, J = 34.8, 1H), 4.41-4.24 (m, 1H), 3.95 (dd, J =11.3, 3.8, 2H), 3.47 (t, J = 11.4, 2H), 2.81 (s, 3H), 2.19 (d, J = 30.4,3H), 2.07-1.93 (m, 2H), 1.75 (d, J = 12.7, 2H). 0.0087 3622-(3-methyl-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

314.1 0.086 363 2-(1-ethyl-5- methyl-1H- pyrazol-4- ylamino)-4-(ethylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.08 (m, 1H), 8.21 (m, 1H), 7.70-7.28 (m, 2H),4.01 (q, J = 7.2, 2H), 3.33 (m, 2H), 2.19 (m, 3H), 1.27 (t, J = 7.2,3H), 1.08 (m, 3H). 0.0060 364 2-(1-(4- fluorophenyl)-3- methyl-1Hpyrazol-4- ylamino)-4- (ethylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.17 (d, J = 125.4, 1H), 8.12 (d, J = 107.0,2H), 7.55 (s, 3H), 7.35 (t, J = 8.7, 2H), 2.86 (s, 3H), 2.26 (s, 3H).0.0019 365 2-(1- (difluoromethyl)-3- methyl-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

280.1 0.035 366 2-(5-methyl-1- propyl-1H-pyrazol- 4-ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

272.2 0.0054 367 2-(1-(3,5- difluorophenyl)-3- methyl-1H- pyrazol-4-ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

342.2 0.0018 368 2-(1-(4- chlorophenyl)-3- methyl-1H- pyrazol-4-ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.75(d, J = 8.6, 2H), 7.67 (s, 1H), 7.50 (d, J = 8.9, 2H), 2.91 (d, J = 4.4,3H), 2.26 (s, 3H). 0.082 369 2-(1-(4- chlorophenyl)-5- methyl-H-pyrazol-4- ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

340.1 0.0025 370 2-(3-methyl-1- (pyridin-2-yl)-1H- pyrazol-4-ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 8.94 (s, 1H), 8.53-8.24 (m, 2H),7.92 (t, J = 7.7, 1H), 7.84 (t, J = 6.7, 1H), 7.69 (s, 1H), 7.32-7.21(m, 1H), 2.93 (s, 3H), 2.31 (s, 3H). 0.0415 371 4-(ethylamino)-2-(5-methyl-1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4- ylamino)pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 137.5, 1H), 8.21 (s, 1H), 7.77-7.30 (m, 2H), 4.41-4.27 (m, 1H), 3.95 (dd, J = 11.2, 4.0, 2H), 3.47 (t,J = 11.3, 2H), 2.23 (s, 3H), 2.00 (qd, J = 12.4, 4.5, 2H), 1.75 (dd, J =12.6, 2.2, 2H), 1.08 (s, 3H). 0.0052 372 4-(ethylamino)-2- (3-methyl-1-(tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4- ylamino) pyrimidine-5-carbonitrile

1H NMR (400 MHz, DMSO) δ 8.97 (d, J = 158.8, 1H), 8.24 (s, 1H), 7.84 (d,J = 58.8, 1H), 7.52 (d, J = 79.5, 1H), 4.31-4.17 (m, 1H), 4.01-3.86 (m,2H), 3.43 (dd, J = 23.6, 12.1, 4H), 2.10 (d, J = 27.9, 3H), 1.89 (dt, J= 20.4, 11.9, 4H), 1.13 (t, J = 7.1, 3H). 0.024 373 4-(ethylamino)-2-(3-methyl-1- (oxetan-3-yl)-1H- pyrazol-4- ylamino) pyrimidine-5-carbonitrile

1H NMR (400 MHz, DMSO) δ 9.32* (s, 1H), 8.94† (s, 1H), 8.29 (s, 1H),8.10* (s, 1H), 7.89† (s, 1H), 7.71* (s, 1H), 7.54† (s, 1H), 5.48 (p, J =7.0, 1H), 4.90- 4.87 (m, 4H), 3.43 (br s, 2H), 2.28-2.11 (m, 3H), 1.17(t, J = 7.1, 3H). [* and ^(†) denote rotameric peaks.] 300 0.0228 3742-(1-isopropyl-5- methyl-1H- pyrazol-4- ylamino)-4- (methylamino)pyrimidine-5- carbonitrile

¹H NMR (500 MHz, DMSO) δ 8.68 (s, 1H), 8.15 (s, 1H), 7.54 (s, 1H),7.17-7.19 (m, 1H), 4.40-4.47 (m, 1H), 2.84 (d, J = 7.5, 3H), 2.16 (s,3H), 1.29-1.36 (m, 6H). 0.0158 375 2-(1,5-dimethyl- 1H-pyrazol-4-ylamino)-4- methoxy- pyrimidine-5- carbonitrile

0.145 376 2-(1,5-dimethyl- 1H-pyrazol-4- ylamino)-4-(2,2,2-trifluoroethylamino) pyrimidine-5- carbonitrile

312 0.0275 377 2-(1-ethyl-5- methyl-1H- pyrazol-4- ylamino)-4-methoxypyrimidine- 5-carbonitrile

259 0.075 378 4-(2,2- difluoroethylamino)- 2-(1,5-dimethyl-1H-pyrazol-4- ylamino)pyrimidine- 5-carbonitrile

294 0.033 378 2-(1,5-dimethyl- 1H-pyrazol-4- ylamino)-4-(2,2,2-trifluoroethoxy) pyrimidine-5- carbonitrile

0.54 380 2-(1- (cyclopropylmethyl)- 3-methyl-1H- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

H NMR (500 MHz, DMSO) δ 8.74 (s, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.23(s, 1H), 3.90 (d, J = 11.5, 2H), 2.89 (d, J = 7.5, 2H), 2.17 (s, 3H),1.14-1.22 (m, 1H), 0.48-0.54 (m, 2H), 0.28-0.33 (m, 2H). 0.045 3812-(1-(4,4- difluorocyclohexyl)- 5-methyl-1H- pyrazol-4- ylamino)-4-(methylamino) pyrimidine-5- carbonitrile

¹H NMR (500 MHz, DMSO) δ 8.71 (m, 1H), 8.32 (s, 1H), 7.58 (s, 1H), 7.19(m, 1H), 4.33 (m, 1H), 2.83 (d, J = 8.0, 3H), 1.90-2.19 (m, 11H). 0.011382 2-(3-methyl-1- (oxetan-3-yl)-1H- pyrazol-4- ylamino)-4-(2,2,2-trifluoroethylamino) pyrimidine-5- carbonitrile

354.1 0.066 383 2-(5-chloro-1- (tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4- ylamino)-4- (methylamino) pyrimidine-5- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.12 (m, 1H), 8.25 (s, 1H), 7.73 (m, 2H), 4.59-4.41 (m, 1H), 3.96 (m, 2H), 3.49 (m, 2H), 2.80 (s, 3H), 2.13-1.92 (m,2H), 1.81 (m, 2H). 0.0096 384 2-(1- Difluoromethyl-5- methyl-1H-pyrazol-4- ylamino)-4- methylamino- pyrimidine-5- carbonitrile

0.0191 385 2-(1,5-Dimethyl- 1H-pyrazol-4- ylamino)-4- ethylamino-pyrimidine-5- carbonitrile

0.0127 386 2-[1-(4-Fluoro- phenyl)-5-methyl- 1H-pyrazol-4- ylamino]-4-methylamino- pyrimidine-5- carbonitrile

0.0959 387 4-Methylamino-2- (3-methyl-1- propyl-1H-pyrazol- 4-ylamino)-pyrimidine-5- carbonitrile

0.0054 388 4-Methylamino-2- (5-methyl-1- oxetan-3-yl-1H- pyrazol-4-ylamino)- pyrimidine-5- carbonitrile

0.0322 389 4-Methylamino-2- (3-methyl-1- oxetan-3-yl-1H- pyrazol-4-ylamino)- pyrimidine-5- carbonitrile

0.0372 390 2-[1-(3,5-Difluoro- phenyl)-5-methyl- 1H-pyrazol-4-ylamino]-4- methylamino- pyrimidine-5- carbonitrile

0.241 391 4-(2,2-Difluoro- ethoxy)-2-(1,5- dimethyl-1H- pyrazol-4-ylamino)- pyrimidine-5- carbonitrile

0.211 392 2-[1-(4,4-Difluoro- cyclohexyl)-3- methyl-1H- pyrazol-4-ylamino]-4- methylamino- pyrimidine-5- carbonitrile

0.266

Example 393(5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone

Step 1 Methyl5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate

To a 30 mL microwave vial was added 0.98 g of2,5-dichloro-N-methylpyrimidin-4-amine, 0.78 g of methyl5-amino-1-methyl-1H-pyrazole-3-carboxylate, 10 mL of 1-butanol and 0.13mL of 4M hydrogen chloride in dioxane. The vial was capped and thereaction was heated in a microwave for 30 minutes at 130° C. As thereaction cooled, a precipitate fell out. Filter the precipitate andrinse with a small amount of n-butanol. Drying the cake yielded 0.964 gof methyl5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylatewhich was used without further purification.

Step 25-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylicacid

To a 100 mL round bottom flask equipped with a stir bar was added 0.964g of methyl5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate,0.28 g of LiOH, 15 mL of tetrahydrofuran and 10 mL of water. Thereaction was stirred at room temperature for 18 hours. Thetetrahydrofuran was removed in vacuo and the aqueous layer was acidifiedto pH 5 with 1N HCl. The aqueous layer was partitioned with ethylacetate and the organic layer washed with brine, dried over MgSO₄,filtered and concentrated to give 0.58 g of5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylicacid which was used without further purification.

Step 3(5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone

To a 100 mL round bottom flask equipped with a stir bar was added 0.116g of5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylicacid, 0.19 g of o-benzotriazol-1-yl-tetramethyluroniumhexafluorophosphate, 0.14 mL of diisopropylethylamine and 2 mL ofdimethylformamide. After pre-activating for 10 minutes, 0.05 mL ofmorpholine was added and the reaction stirred at room temperature for 2hours. The reaction was concentrated and purified by preparative reversephase HPLC to yield 53.2 mg of(5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone.LCMS (Method A): [MH⁺]=352.0 at 2.80 min. ¹H-NMR (DMSO): δ 9.47 (s, 1H),7.86 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 3.74 (s, 3H), 3.61 (m, 8H),2.88 (d, 3H). K₁=0.16.

Example 3942-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile

Step 1: 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide

To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoicacid (2.5 g, 11.7 mmol) in CH₂Cl₂ (50 mL) was added dropwise of oxalylchloride (2.97 g, 23.4 mmol). The reaction was stirred at ambienttemperature for about 2 hours, then concentrated under reduced pressureto remove the solvent, the remained solid was dissolved in THF (30 mL)and was added dropwise into NH₄OH (50 mL), the reaction was stirred atambient temperature for 1 hour. The solution was concentrated underreduced pressure and portioned between EtOAc (50 mL) and water (100 mL),the aqueous phase was extracted with EtOAc, and the combined organic waswashed with sat. NH₄Cl (50 mL), dried over anhydrous Na₂SO₄, filletedand concentrated to give crude2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 100%)as white solid which was used in the next step without furtherpurification.

Step 2: 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide

To a solution of2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 11.7mmol) in MeOH (50 mL) was added Pd/C (1 g), exchanged with nitrogen forthree times then with hydrogen, and the reaction was stirred at hydrogenatmosphere (1 atm) for 1 h at ambient temperature. The solution wasfiltered and the filtrate was concentrated under reduced pressure togive crude 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (2.0g, 93%) which was used in the next step without further purification.

Step 3:2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide

To a solution of2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (250 mg, 1.37mmol) in 2-methoxyethanol (5 mL) was added2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (290 mg, 1.37mmol) and trifluoroaceticacid (156 mg, 1.37 mmol), the reaction wasstirred at 70° C. for about 0.5 h. The reaction mixture was cooled toambient temperature followed with the addition of water (10 mL) and thepH of solution was adjusted to 8 with sat. Na₂CO₃ The aqueous phase wasextracted with ethyl acetate (10 mL×3), the combined organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated to dry togive a residue which was purified by column chromatography on silica gel(CH₂Cl₂:MeOH=20:1) to give2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide(250 mg, 51%) as white solid. LCMS (m/z) ES+358 (m+H).

Step 4:2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile

A stirred solution of2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide(250 mg, 0.7 mmol) in POCl₃ (5 mL) was stirred at 90° C. for 1 hour.POCl₃ was removed by evaporation, the mixture was added into ice/H₂O (10ml) and the pH of the solution was adjusted to 8 with sat.Na₂CO₃, theaqueous phase was extracted with ethyl acetate (5 mL×3). The combinedorganic phase was washed with sat. sodium chloride (10 mL), dried overanhydrous sodium sulfate, filtered and concentrated to dry to give aresidue which was purified by recrystallization to give2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile(100 mg, 42%) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) δ ppm 9.18 (s,1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.10 (s, 1H), 2.91 (d, 3H), 2.22 (s,3H), 1.94 (s, 2H). LCMS (m/z) ES+340 (m+1). Purity, 99.3% (HPLC at 214nm); K_(i)=0.0005.

Compounds made using the above procedure are shown in Table 10 below,together with low resolution mass spectrometry (M+H), proton NMR, andLRRK2 K_(i) (micromolar) data for selected compounds determined from theassay described below.

TABLE 10 Name Structure ¹H NMR M + H⁺ K_(I) 395 N,N-dimethyl-2-(5-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidim-2-ylamino)-1H- pyrazol-1- yl)acetamide

¹H NMR (300 MHz, CD₃OD) δ ppm 8.08 (s, 1H), 7.79 (br s, 1H), 5.24 (br s,1H), 4.92 (s, 2H), 3.12 (s, 3H), 3.04 (s, 3H), 3.00 (s, 3H), 2.24 (s, 3H) 0.015 396 N,N-dimethyl-2- (3-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)acetamide

¹H NMR (300 MHz, CD₃OD) δ ppm 8.11 (s, 1H), 7.96 (s, 1H), 5.23 (b rs,1H), 4.90 (s, 2H), 3.08 (s, 3H), 3.07 (s, 3H), 2.99 (s, 3H), 2.27 (s, 3H) 0.004 397 N-methyl-2-(3- methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)acetamide

¹H NMR (300 MHz, CD₃OD) δ ppm 8.14 (s, 1H), 7.94 (s, 1 H), 6.19 (brs, 1H), 5.26 (brs, 1 H), 4.73 (s, 2 H), 3.07 (d, J = 4.8 Hz, 3 H), 2.81 (d,J = 4.8 Hz, 3 H), 2.32 (s, 3 H) 0.0095 398 N-methyl-2-(5- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)acetamide

¹H NMR (300 MHz, CDCl₃) δ 8.14 (s, 2H), 6.17 (s, 1H), 5.26 (s, 1H), 3.07(d, J = 4.6 Hz, 3H), 2.73 (d, J = 4.8 Hz, 3H), 2.32 (s, 3H), 1.84 (s,6H) 0.003 399 N,N,2-trimethyl-2- (5-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 6.85(s, 1H), 2.84 (s, 6H), 2.38 (s, 3H), 2.02 (s, 3H), 1.67 (s, 6H). 0.314400 2-methyl-2-(5- methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-1- (pyrrolidin-1-yl)propan-1-one

1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 6.92(s, 1H), 3.35 (t, J = 6.6, 2H), 2.81 (s, 3H), 2.53 (s, 1H), 2.03 (s,3H). 0.404 401 2-methyl-2-(5- methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H-NMR (300 MHz, DMSO- d₆) δ ppm 9.18 (s, 1H), 8.29 (s, 1H), 8.14 (s,1H), 7.10 (s, 1H), 2.91 (d, 3H), 2.22 (s, 3H), 1.94 (s, 2H) 0.0007 4021-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)cyclopropane- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.12 (s, 2H), 7.03 (s, 1H), 2.91(d, J = 4.4, 3H), 2.16 (s, 3H), 1.87-1.78 (m, 2H), 1.78-1.70 (m, 2H).0.0037 403 (R)-2-(3-methyl-4- (4-(methylamino)- 5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-1- (pyrrolidin-l-yl)propan-1-one

398 0.016 404 (R)-N,N-dimethyl- 2-(3-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

¹H-NMR (500 MHz, DMSO) δ 9.04 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.04(s, 1H), 5.39 (q, J = 6.5 Hz, 1H), 2.97 (s, 3H), 2.87 (s, 3H), 2.82 (s,3H), 2.14 (s, 3H), 1.45 (d, J = 6.5 Hz, 3H). 0.018 405 (S)-2-(3-methyl-4(4-(methylamino)- 5- (trifluoromethyl) pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-1- (pyrrolidin-1- yl)propan-1-one

¹H NMR (500 MHz, DMSO) δ 9.08 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.02(s, 1H), 5.16-5.20 (m, 1H), 3.53-3.57 (m, 1H), 3.23-3.31 (m, 3H), 2.88(d, J = 4.0, 3H), 2.13 (s, 3H), 1.83- 1.88 (m, 2H), 1.67-1.79 (m, 2H),1.48 (d, J = 6.5, 3H). 0.022 406 3-(5-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H NMR (500 MHz, MeOD) δ 7.96 (s, 1H), 7.67 (s, 1H), 4.34-4.37 (m, 2H),2.96-2.99 (m, 2H), 2.91 (s, 3H), 2.27 (s, 3H). 0.0073 4073-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H NMR (500 MHz, CDCl₃) δ 8.12 (s, 1H), 7.97 (s, 1H), 4.30-4.33 (m, 2H),3.07 (s, 3H), 2.90-2.93 (m, 2H), 2.26 (s, 3H), 1.64 (s, 2H). 0.0054 408methyl 2-methyl- 2-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanoate

1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.03(s, 1H), 3.61 (s, 3H), 2.89 (d, J = 4.4, 3H), 2.14 (s, 3H), 1.71 (s,6H). 0.0047 409 methyl 2-methyl- 2-(5-methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanoate

1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 6.94(s, 1H), 3.70 (s, 3H), 2.83 (s, 3H), 2.05 (s, 3H), 1.71 (s, 6H). 0.0076410 2-(3-ethyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1-yl)-2- methylpropanenitrile

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 6.98(s, 1H), 2.97 (s, 2H), 2.84 (s, 3H), 1.95 (s, 6H), 1.13 (t, J = 7.4,3H). 0.010 411 (R)-2-(5-methyl-4- (4-(methylamino)- 5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-1- (pyrrolidin-1-yl)propan-1-one

¹H-NMR (500 MHz, MeOD) δ 7.88 (s, 1H), 7.53 (s, 1H), 7.49-5.19 (m, 1H),3.35-3.39 (m, 1H), 2.77-2.81 (m, 3H), 2.69-2.71 (m, 1H), 2.13 (s, 3H),1.75-1.84 (m, 3H), 1.66- 1.71 (m, 1H), 1.50 (d, J = 7.0, 1H). 0.039 412(R)-N,N-dimethyl- 2-(5-methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

¹H-NMR (500 MHz, DMSO) δ 8.88 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 6.95(s, 1H), 5.37 (q, J = 6.0 Hz, 1H), 2.79 (s, 6H), 2.74 (s, 3H), 2.15 (s,3H), 1.43 (d, J = 6.0 Hz, 3H). 0.0284 413 (S)-2-(5-methyl-4-(4-(methylamino)- 5- (trifluoromethyl) pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-1- (pyrrolidin-1- yl)propan-1-one

¹H NMR (500 MHz, DMSO) δ 8.08 (s, 1H), 7.79 (d, J = 10.0, 1H), 6.56-6.52(m, 1H), 5.15 (s, 1H), 5.08-5.12 (m, 1H), 3.48-3.56 (m, 2H), 3.27-3.32(m, 1H), 2.99 (d, J = 4.5, 3H), 2.84 (d, J = 4.0, 1H), 2.21 (t, J = 9.5,3H), 1.81-1.88 (m, 4H), 1.74-1.79 (m, 3H). 0.040 414 (S)-N,N-dimethyl-2-(5-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)propanamide

¹H NMR (500 MHz, DMSO) δ 8.48 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H),6.64-6.66 (m, 1H), 5.33-5.36 (m, 1H), 2.77- 2.85 (m, 9H), 2.16 (s, 3H),1.48-1.51 (m, 3H). 0.030 415 (S)-2-(5-methyl-4- (4-(methylamino)- 5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H NMR (500 MHz, DMSO) δ 8.60 (s, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 6.71(s, 1H), 5.73-5.75 (m, 1H), 2.87-2.98 (m, 3H), 2.26 (s, 3H), 1.75- 1.78(s, 3H). 0.0095 416 (S)-2-(3-methyl-4- (4-(methylamino)- 5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H NMR (500 MHz, DMSO) δ 8.25-8.26 (m, 1H), 8.10 (s, 1H), 8.03 (s, 1H),6.75 (s, 1H), 5.68-5.69 (m, 1H), 2.92-2.93 (m, 3H), 2.19 (s, 3H), 1.76-1.78 (m, 3H). 0.0019 417 2-(4-(5-chloro-4- (methylamino)pyrimidin-2-ylamino)- 3-methyl-1H- pyrazol-1-yl)-2- methylpropanenitrile

1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.09(d, J = 4.5, 1H), 2.89 (d, J = 4.6, 3H), 2.18 (s, 3H), 1.91 (s, 6H).0.0021 418 2-(5-chloro-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropanenitrile

1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.06(s, 1H), 2.83 (s, 3H), 2.01 (s, 6H). 0.0019 419 2-(3-cyclopropyl- 4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-2- methylpropanenitrile

1H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.05(s, 1H), 2.91 (d, J = 4.4, 3H), 2.12 (s, 1H), 1.89 (s, 6H), 0.92-0.80(m, 2H), 0.80-0.64 (m, 2H). 0.0010 420 2,2-dimethyl-3-(3- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)propanenitrile

¹H-NMR (500 MHz, CDCl₃) δ 8.03 (s, 2H), 7.05 (br, s, 1H), 5.20 (d, J =1.5 Hz, 1H), 4.08 (s, 2H), 3.01 (s, 3H), 2.18 (s, 3H), 1.40 (m, 6H)0.0028 421 2,2-dimethyl-3-(5- methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanenitrile

¹H-NMR (500 MHz, CDCl₃) δ 8.01 (s, 1H), 7.73 (br, s, 1H), 5.10 (s, 1H),4.09 (s, 2H), 2.93 J = 4.5 Hz, 3H), 2.27 (s, 3H), 1.40 (s, 6H) 0.0068422 1-(5-chloro-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)cyclopropane- carbonitrile

1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.06(t, J = 6.9, 1H), 2.84 (s, 2H), 2.10-1.98 (m, 1H), 1.89-1.76 (m, 1H).0.0023 423 N-tert-butyl-2- methyl-2-(3- methyl-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

1H-NMR (500 MHz, DMSO) δ 9.101 (s, 1H) 8.081-8.143 (m, 2H), 7.025-7.049(m, 1H), 6.348 (s, 1H), 2.877 (d, J = 4.0, 3H), 2.193 (s, 3H), 1.644 (s,6H), 1.177 (s, 9H). 0.073 424 2-methyl-2-(3- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-N- trifluoroethyl) propanamide

0.0063 425 2-(5-chloro-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-N- ethyl-2-methyl propanamide

1H NMR (400 MHz, DMSO) δ 8.35 (d, J = 9.1, 1H), 8.22 (s, 1H), 8.16 (s,1H), 7.34 (d, J = 8.5, 2H), 6.32 (t, J = 9.5, 1H), 3.54 (s, 3H), 2.94(d, J = 4.4, 3H). 0.0355 426 N- (cyclopropylmethyl)- 2-methyl-2-(5-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)propanamide

1H-NMR (500 MHz, MeOD) δ 7.50-8.10 (m, 2H), 3.05 (d, J = 7.0 Hz, 3H),2.97 (s, 3H), 2.16 (s, 3H), 1.76 (s, 6H), 0.99-1.23 (m, 1H), 0.43-0.47(m, 2H), 0.19-0.22 (m, 2H). 0.009 427 N- (cyclopropylmethyl)-2-methyl-2-(3- methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

1H-NMR (500 MHz, MeOD) δ 7.82-8.20 (m, 2H), 3.03 (d, J = 6.5 Hz, 3H),2.98 (s, 3H), 2.20 (s, 3H), 1.76 (s, 6H), 0.93-0.94 (m, 1H), 0.39-0.44(m, 2H), 0.13-0.18 (m, 2H). 0.052 428 N-ethyl-1-(3- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- yl)cyclobutane-carboxamide

398.2 0.024 429 N-isopropyl-2- methyl-2-(5- methyl-4-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1-yl)propanamide

430 1-(3-methyl-4-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- pyrazol-1- yl)cyclobutane- carbonitrile

352.1 431 2-(4-(4- (cyclopropylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-3- methyl-1H- pyrazol-1-yl)-2- methylpropanenitrile

432 N,2-dimethyl-2-(3- methyl-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1- yl)propanamide

1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.17(s, 1H), 7.01 (s, 1H), 2.93 (d, 3H), 2.55 (d, 3H), 2.17 (s, 3H). 1.64(s, 6H). 372.1 0.0184 433 1-(5-chloro-4-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)-1H- pyrazol-1- yl)cyclopropane-carbonitrile

358.1 434 2-[4-(5-Chloro-4- methoxy- pyrimidin-2- ylamino)-5-methyl-pyrazol-1- yl]-2-methyl- propionic acid methyl ester

0.0122 435 2-[4-(5-Chloro-4- methoxy- pyrimidin-2- ylamino)-3-methyl-pyrazol-1- yl]-2-methyl- propionic acid methyl ester

0.0355 436 (S)-N,N-Dimethyl- 2-[3-methyl-4-(4- methylamino-5-trifluoromethyl- pyrimidin-2- ylamino)-pyrazol- 1-yl]- propionamide

0.0303 437 R)-2-[3-Methyl-4- (4-methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]-propionitrile

0.0065 438 2-[4-(5-Chloro-4- methoxy- pyrimidin-2- ylamino)-3-cyclopropyl- pyrazol-1-yl]-2- methyl- propionitrile

0.0058 439 (R)-2-[5-Methyl-4- (4-methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]-propionitrile

0.0016 440 N-Ethyl-2-[3- methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- isobutyramide

0.0095 441 N-Ethyl-2-[5- ethyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- isobutyramide

0.0237 442 1-[5-Methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- cyclobutane- carboxylic acidethylamide

0.0156 443 2-[5-Methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]-N-(2,2,2- trifluoro-ethyl)-isobutyramide

0.0666 444 N-Isopropyl-2-[3- ethyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- isobutyramide

0.0246 445 N-Methyl-2-[5- ethyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- isobutyramide

0.0926 446 1-[5-Methyl-4-(4- methylamino-5- trifluoromethyl-pyrimidin-2- ylamino)-pyrazol- 1-yl]- cyclobutane- carbonitrile

0.0024 447 N-tert-Butyl-2-[5- methyl-4-(4- methylamino-5-trifluoromethyl- pyrimidin-2- ylamino)-pyrazol- 1-yl]- isobutyramide

0.067 448 2-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-5- methyl-pyrazol-1- yl]-N-methyl- isobutyramide

0.0153 449 2-[4-(4- Cyclopropylamino- 5-trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-N-methyl- isobutyramide

1H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.21(d, J = 4.1, 1H), 6.98 (s, 1H), 2.83 (s, 1H), 2.54 (d, J = 4.3, 3H),2.20 (s, 3H), 1.61 (s, 6H), 0.69 (dd, J = 35.4, 4.3, 4H). 0.0013 4502-[4-(4- Cyclopropylamino- 5-trifluoromethyl- pyrimidin-2- ylamino)-5-methyl-pyrazol-1- yl]-N-methyl- isobutyramide

0.0071 451 2-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2-ylamino)-3- methyl-pyrazol-1- yl]-2-methyl- propionitrile

1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.15 (d, J = 26.9, 2H), 7.05 (s,1H), 3.51- 3.42 (m, 2H), 2.19 (s, 3H), 1.92 (s, 6H), 1.13 (t, J = 7.1,3H). 0.0003 452 2-(3-chloro-4-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- pyrazol-1-yl)-2- methylpropanenitrile

453 2-[4-(4- Ethylamino-5- trifluoromethyl- pyrimidin-2- ylamino)-3-methyl-pyrazol-1- yl]-N-methyl- isobutyramide

0.0092

Example 454 In Vitro LRRK2 Lanthascreen Binding Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In 384 well proxiplates F black, shallow well plates LRRK2,Eu-anti-GST-antibody, Alexa Fluor® Kinase tracer 236 and test compoundwere incubated together.

Binding of the Alexa Fluor® “tracer” to a kinase is detected by additionof a Eu-labeled anti-GST antibody. Binding of the tracer and antibody toa kinase results in a high degree of FRET, whereas displacement of thetracer with a kinase inhibitor results in a loss of FRET.

Assay conditions and materials used were as follows:

Final Assay Conditions:

GST-LRRK2 G2019S 10 nM Eu-anti-GST-antibody 2 nM Kinase tracer 236 8.5nM Kinase reaction time: 1 hour Temperature: ambient Total volume: 15 μlDMSO 1%

Materials:

384 well proxiplates F black Perkin Elmer cat# 6008260 shallow wellKinase: LRRK2G2019S, Invitrogen cat # PV4882 (LOT 567054A). Eu-labeledanti-GST antibody Invitrogen cat # PV5594 Alexa Fluor ® Kinase tracer236 Invitrogen cat #PV5592 TRIS- HCl Sigma cat # T3253 EGTA Sigma cat #E3889 Brij-35: Sigma cat # B4184(30% w/v) DMSO: Sigma cat # D8418 MgCl₂Sigma cat # M9272 Reaction Buffer: H₂O/50 mM Tris, pH 7.4/10 mM MgCl₂/1mM EGTA/0.01% Brij 35

Compound Plate Preparation:

Serially dilute test compounds (10 mM stock) 1:3.16 (20 ul+43.2 ul) in100% DMSO. 12 pt curve. Dilute each concentration 1:33.3 (3 ul+97 ul) inreaction buffer. Stamp 5 ul to assay plate. Final top test concentration100 uM

Total and Blank Preparation:

In Reaction Buffer, 5 ul of DMSO (3%) was added to total and blank wellsand 5 ul of Eu-labeled anti-GST antibody (6 nM) was added to blankwells. Add 5 ul LRRK2 (30 nM)/Eu-labeled anti-GST antibody (6 nM) mix tocompound and total wells.

Assay Procedure:

Add 5 ul kinase tracer (25.5 nM) to all wells. Incubate plates at roomtemperature for 1 hour on a plate shaker (gentle shaking). Read onPerkin Elmer EnVision reader HTRF protocol

Data Handling:

Calculate ratio: (665/620)*10000. Substract mean background values fromall data points. Calculate % of control for each test value. Plot % ofcontrol vs Compound concentration. Calculate Ki Value (xlfit curvefitting—Morrison equation). Results expressed as a Ki in μM. Equationfor Ki:

Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et)))

Where Et=4 nM kd (Tracer)=8.5 nM

Tracer concentration (S)=8.5 nM

Example 455 In Vitro LRRK2 Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In a polypropylene plate, LRRK2, fluorescently-labeled peptidesubstrate, ATP and test compound were incubated together. Using aLabChip 3000 (Caliper Life Sciences), after the reaction the substratewas separated by capillary electrophoresis into two populations:phosphorylated and unphosphorylated. The relative amounts of each werequantitated by fluorescence intensity. LRRK2 Ki was determined accordingto the equation:

Y=V0*(1−(x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et))).

Ki values in Table 4 and elsewhere herein are shown in μM.

Assay conditions and materials used were as follows:

Final Assay Conditions:

LRRK2 G2019S in 5 mM MgCl₂: 5.2 nM (Invitrogen lot # 567054A) LRRK2G2019S in 1 mM MnCl₂: 11 nM (Invitrogen lot # 567054A) LRRK2 Wild typein 5 mM MgCl₂: 15 nM (Invitrogen lot # 500607F) LRRK2 I2020T in 5 mMMgCl₂: 25 nM (Invitrogen lot # 43594) Substrate: 1 μM ATP: 130 μM Kinasereaction time: 2 hours Temperature: ambient Total volume: 20 μl

ATP^(app) Kms:

G2019S in 5 mM MgCl₂: 130 μM G2019S in 1 mM MnCl₂: 1 μM Wild type in 5mM MgCl₂: 80 μM I2020T in 5 mM MgCl₂: 14 μM

Materials:

Solid Support: Black 50 μL volume polypropylene 384 well plate (MatriCalcat # MP101-1-PP) Kinase: LRRK2 G2019S (Invitrogen cat # PV4882). LRRK2Wild type (Invitrogen cat # PV4874). Substrate:5FAM-GAGRLGRDKYKTLRQIRQ-CONH₂ Non-binding plate: 384 well clear V-bottompolypropylene plates (Greiner cat # 781280). ATP: 10 mM ATP (CellSignaling cat # 9804). Triton X-100: Triton X-100. Brij-35: Brij-35(Pierce cat # 20150). Coating Reagent #3: Coating Reagent #3 (Caliper).DMSO: DMSO (Sigma cat # 34869-100ML). Complete Reaction H₂O/25 mM Tris,pH 8.0/5 mM Buffer: MgCl₂/2 mM DTT/0.01% Triton X-100. Stop Solution:H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% Coating Reagent #3/20 mMEDTA. Separation Buffer: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.1%Coating Reagent #3/1:200 Coating Reagent #8/10 mM EDTA/5% DMSO.

Compound Plate Preparation:

For serial dilutions, 34.6 μl DMSO was added to columns 3-24. For theassay controls, 37.5 μl DMSO was added to columns 1 and 2 of rows A andP. a, d and 50 μl 25 μM G-028831 (Staurosporine) was added to columns 1and 2, row B. For the samples: to start at 100 μM, 37.5 μl DMSO was tocolumns 1 and 2, then 12.5 μl 10 mM compound; to start at 10 μM, 78 μlDMSO was added to columns 1 & 2, then 2 μl 10 mM compound; and to startat 1 μM, 25 μM compound (2 μl 10 mM cmpd+798 μl DMSO) was added to emptycolumns 1 and 2. A Precision instrument was used to perform 1:3.16serial dilutions (“PLK_BM_serial_halflog”).

ATP Preparation:

ATP was diluted to 282.1 μM in Complete Kinase Buffer (finalconcentration was 130 μM).

Total and Blank Preparation:

In Complete Reaction Buffer, substrate was diluted to 4 μM. Equalvolumes of Complete Reaction Buffer and 4 μM substrate were combined toobtain the blank. Equal volumes of Complete Reaction Buffer and 4 μMsubstrate were combined and to the combined solution was added 2× finalLRRK2 concentration.

Assay Procedure:

To a 50 μl polypropylene plate, 5 μl/well buffer/substrate was added byhand to Blank wells. A Biomek FX was used to start the kinase reaction(“PLK SAR 23 ATP”). The following were added to the appropriate wells:

2 μl compound+23 μl ATP;

5 μl/well compound/ATP in Assay Plate;

5 μl/well kinase/substrate in Assay Plate;

The plate was incubated for 2 hours in the dark. Biomek FX was used tostop the kinase reaction (“PLK Stop”), and 10 μl/well Stop solution wasadded to the Assay Plate. Results were read on the LabChip 3000.

Lab Chip 3000 Protocol:

The LabChip 3000 was run using the job “LRRK2 IC50” with the followingjob settings:

Pressure: −1.4 psi Downstream voltage: −500 V Upstream voltage: −2350 VPost sample buffer sip time: 75 seconds Post dye buffer sip time: 75seconds Final delay time: 200 seconds

Example 456 Parkinson's Disease Mouse Model

Parkinson's disease can be replicated in mice and in primates byadministration of 1-methyl-4-phenyul tetrahydropyridine (MPTP), aselective nigrostriatal dopaminergic neurotoxin that produces a loss ofstriatal dopamine (DA) nerve terminal markers. Compounds of theinvention may be evaluated for effectiveness in treatment of Parkinson'sdisease using MPTP induced neurodegeneration following generally theprotocol described by Saporito et al., J. Pharmacology (1999) Vol. 288,pp. 421-427.

Briefly, MPTP is dissolved in PBS at concentrations of 2-4 mg/ml, andmice (male C57 weighing 20-25 g) are given a subcutaneous injection of20 to 40 mg/kg. Compounds of the invention are solubilized withpolyethylene glycol hydroxystearate and dissolved in PBS. Mice areadministered 10 ml/kg of compound solution by subcutaneous injection 4to 6 h before MPTP administration, and then daily for 7 days. On the dayof the last injection, mice are sacrificed and the midbrain blocked andpostfixed in paraformaldehyde. Striata are dissected free, weighed, andstored at −70° C.

The striata thus collected are evaluated for content of dopamine and itsmetabolites dihydroxyphenylacetic acid and homovanillic acid, by HPLCwith electrochemical detection as described by Sonsalla et al., J.Pharmacol. Exp. Ther. (1987) Vol. 242, pp. 850-857. The striata may alsobe evaluated using the tyrosine hydroxylase assay of Okunu et al., AnalBiochem (1987) Vol. 129, pp. 405-411 by measuring ¹⁴CO₂ evolutionassociated with tyrosine hydroxylase-mediated conversion of labeledtyrosine to L-dopa. The striata may further be evaluated using theMonoamine oxidase-B assay as described by White et al., Life Sci.(1984), Vol. 35, pp. 827-833, and by monitoring dopamine uptake asdescribed by Saporito et al., (1992) Vol. 260, pp. 1400-1409.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is: —NR^(a)—;or —O— wherein R^(a) is hydrogen or C₁₋₆alkyl; R¹ is: C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with C₁₋₆alkyl; heterocyclyloptionally substituted one or more times with R⁷; orheterocyclyl-C₁₋₆alkyl optionally substituted one or more times with R⁷;or X and R¹ together form C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶; or R¹ and R^(a)together with the atoms to which they are attached may form a three- tosix-membered heterocyclic ring optionally substituted one or more timeswith R⁷; R² is: C₁₋₆alkyl; halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl;C₂₋₆alkenyl; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted one or more timeswith R⁶; —OR^(b) wherein R^(b) is C₁₋₆alkyl, C₃₋₆cycloalkyl optionallysubstituted one or more times with R⁶, or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted one or moretimes with R⁶; or —C(O)—R^(c) wherein R^(c) is C₁₋₆alkyl, C₁₋₆alkoxy,amino, or heterocyclyl optionally substituted one or more times with R⁷;R³ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano-C₁₋₆alkyl;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfonylC₁₋₆alkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶;C₃₋₆cycloalkyl-sulfonyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted one or more times with R⁶; heterocyclyl optionallysubstituted one or more times with R⁷; heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷; aryl optionally substituted one or more times with R⁸;aryl-C₁₋₆alkyl wherein the aryl portion is optionally substituted one ormore times with R⁸; heteroaryl optionally substituted one or more timeswith R⁸; heteroaryl-C₁₋₆alkyl wherein the heteroaryl portion isoptionally substituted one or more times with R⁸; or —Y—C(O)—R^(d); Y isC₂₋₆alkylene or a bond; R^(d) is C₁₋₆alkyl, C₁₋₆alkoxy, amino,C₁₋₆alkyl-amino, di-C₁₋₆alkyl-amino, halo-C₁₋₆alkyl-amino,di-halo-C₁₋₆alkyl-amino, halo-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, hydroxy,C₁₋₆alkoxy-C₁₋₆alkyl, cyano-C₁₋₆alkyl, C₁₋₆alkylsulfonylC₁₋₆alkyl,amino-C₁₋₆alkyl, C₃₋₆cycloalkyl optionally substituted one or more timeswith R⁶, C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶ heterocyclyl optionallysubstituted one or more times with R⁷, or heterocyclyl-C₁₋₆alkyl whereinthe heterocyclyl portion is optionally substituted one or more timeswith R⁷; R⁴ is: hydrogen; C₁₋₆alkyl; halo; cyano; halo-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted one or moretimes with R⁶; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkylportion is optionally substituted one or more times with R⁶; or—Y—C(O)—R^(d); R⁵ is: hydrogen; or C₁₋₆alkyl; each R⁶ is independently:C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; oxo; cyano; halo; orY—C(O)—R^(d). each R⁷ is independently: C₁₋₆alkyl; halo-C₁₋₆alkyl; halo;oxo; C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkoxy-C₁₋₆alkyl; cyano;—Y—C(O)—R^(d); heterocyclyl; heterocyclyl-C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; or C₃₋₆cycloalkylsulfonyl; and each R⁸ isindependently: oxo; C₁₋₆alkyl; halo-C₁₋₆alkyl; halo; C₁₋₆alkyl-sulfonyl;C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkyl; cyano; hetoeryclyl;heterocyclyl-C₁₋₆alkyl; —Y—C(O)—R^(d); C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, or C₃₋₆cycloalkyl-sulfonyl.
 2. The compound ofclaim 1, wherein X is —NH— or —O—.
 3. The compound of claim 1, whereinR¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.
 4. The compound of claim 1, wherein R¹ isC₁₋₆alkyl.
 5. The compound of claim 1, wherein R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.
 6. Thecompound of claim 1, wherein R² is: halo; halo-C₁₋₆alkyl or cyano. 7.The compound of claim 1, wherein R² is: fluoro; bromo; chloro; iodo;trifluoromethyl; or cyano.
 8. The compound of claim 1, wherein R³ is:C₁₋₆alkyl; halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally one or more times with R⁶;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted one or more times with R⁶; heterocyclyloptionally substituted one or more times with R⁷; heterocyclyl-C₁₋₆alkylwherein the heterocyclyl portion is optionally substituted one or moretimes with R⁷; or —C(O)—R^(d).
 9. The compound of claim 1, wherein R³is: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyloptionally substituted one or more times with R⁷; orheterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion is optionallysubstituted one or more times with R⁷.
 10. The compound of claim 1,wherein R³ is: methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl;cyclopropylmethyl; cyclobutyl; methanesulfonyl; ethylsulfonyl;cyclopropylsulfonyl; sec-butylsulfonyl; morpholin-4-yl-ethyl;oxetan-3-yl; 2-methoxyethyl; 2-hydroxy-2-methyl-propyl;3-hydroxy-2-methyl-propan-2-yl; 2-methoxy-propyl;tetrahydro-2H-pyran-4-yl; tetrahydrofuran-3-yl;2,6-dimethyltetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-3-yl); phenyl;4-(methylsulfonyl)phenyl); 4-cyano-phenyl; 4-fluoro-phenyl;4-chloro-phenyl; 3,5-difluorophenyl; 4-(dimethylamino-carbonyl)-phenyl);4-(cyclopropylsulfonyl)phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl;difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl;1-methyl-cyclopropyl-carbonyl; 3-methylpyridin-4-yl;2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl;pyridin-2-ylmethyl; 1-(pyridin-2-yl)ethyl; cyclopropylsulfonyl;1-cyano-1-methyl-ethyl; 2-cyano-ethyl; 1-cyano-ethyl;2-cyano-2-methyl-propyl; 1-(2,2,2-trifluoroethyl)piperidin-4-yl;1-(methylsulfonyl)azetidin-3-yl; (3-methyloxetan-3-yl)methyl;(1S,5S)-8-oxabicyclo[3.2.1]octan-3-yl; 1-(oxetan-3-yl)piperidin-4-yl;1-acetyl-piperidin-4-yl; 1-(cyclopropyl-carbonyl)-piperidin-4-yl;1-methyl-piperidin-4-yl; 1-methyl-2-oxo-piperidin-5-yl;2-oxo-piperidin-5-yl; 1-(isopropyl-carbonyl)-piperidin-4-yl;1-(oxetan-3-yl)azetidin-3-yl; 1-(cyclopropyl-carbonyl)-piperidin-4-yl;2-methoxycyclopentyl; 3-methoxycyclopentyl;1-methoxy-2-methylpropan-2-yl; tetrahydro-2H-1,1-dioxo-thiopyran-4-yl;3-fluoro-1-(oxetan-3-yl)piperidin-4-yl; 1-methoxypropan-2-yl;1-(2,2,2-trifluoroethyl)azetidin-3-yl); 1-(oxetan-3-yl)pyrrolidin-3-yl;1-isopropylazetidin-3-yl; 3-fluoro-1-methylpiperidin-4-yl;1-ethyl-3-fluoropiperidin-4-yl; 1-methylpyrrolidin-3-yl;2-methoxyethyl)piperidin-4-yl); 1-methyl-1-(methylamino-carbonyl)-ethyl;2-methyl-2-morpholino-propyl; 4,4-difluorocyclohexyl;morpholin-4-yl-carbonyl; dimethylamino-carbonyl-methyl;methylamino-carbonyl-methyl; 1-methyl-1-(dimethylamino-carbonyl)-ethyl;pyrrolidin-′-yl-carbonyl; 1-cyamo-cyclopropyl;1-(pyrrolidin-′-yl-carbonyl)-ethyl; 1-(dimethylamino-carbonyl)-ethyl;1-(methoxy-carbonyl)-ethyl; 1-(tert-butylamino-carbonyl)-1-methyl-ethyl;1-(2,2,2-trifluoroethyllamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-1-methyl-ethyl;1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl;1-(ethylamino-carbonyl)-cyclobutyl;1-(isopropylamino-carbonyl)-1-methyl-ethyl; 1-cyano-cyclobutyl;2-methoxy-1-methyl-ethyl; 1-methyl-1-(methoxy-carbonyl)-ethyl;2-methoxy-2-methyl-propan-1-yl; 1-(oxetan-3-yl)-pyrrolidin-3-yl;isopropylsulfonyl; butane-2-sulfonyl; 1-(2-fluoroethyl)-piperidin-4-yl;3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl;pyridin-3-ylmethyl; 6-methyl-pyridin-2-ylmethyl;2-(morpholin-1-yl)-1,1,dimethyl-ethyl; pyrimdin-2-yl-methyl;3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl; 1-(oxetan-3-yl)-piperidin-3-yl;1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl; pyridazin-3-ylmethyl;piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl-butan-1-yl;1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl; pyrimidin-4-ylmethyl;1-methyl-1H-pyrazol-3-ylmethyl;1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl;1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl;3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl;dimethyl-[1,3]dioxan-5-yl; 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl;2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl;2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-5-yl;2-(4H-1,2,4-triazol-3-yl)propan-2-yl; or 1-methyl-1H-pyrazole-4-yl. 11.The compound of claim 1, wherein R⁴ is hydrogen; C₁₋₆alkyl; halo; orC₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl.
 12. The compoundof claim 1, wherein R⁴ is hydrogen or C₁₋₆alkyl.
 13. The compound ofclaim 1, wherein R⁴ is chloro or methyl.
 14. The compound of claim 1,wherein R⁵ is C₁₋₆alkyl.
 15. The compound of claim 1, wherein R⁵ ishydrogen or methyl.
 16. The compound of claim 1, wherein said compoundsare of formula II


17. The compound of claim 1, wherein said compound is of formula III

and wherein X, R¹, R, R², R³, R⁴ and R⁵ are as recited in claim
 1. 18.The compound of claim 1, wherein said compound is of formula IV

and wherein X, R¹, R, R², R³, R⁴ and R⁵ are as recited in claim
 1. 19.The compound of claim 1, wherein said compound is of formula V

and wherein X, R¹, R, R², R³, R⁴ and R⁵ are as recited in claim
 1. 20. Acomposition comprising: (a) a pharmaceutically acceptable carrier; and(b) a compound of claim
 1. 21. A method for treating Parkinson'sdisease, said method comprising administering to a subject in needthereof an effective amount of a compound of claim 1.